Indazole inhibitors of the wnt signal pathway and therapeutic uses thereof

ABSTRACT

Indazole compounds for treating various diseases and pathologies are disclosed. More particularly, the present invention concerns the use of an indazole compound or analogs thereof, in the treatment of disorders characterized by the activation of Wnt pathway signaling (e.g., cancer, abnormal cellular proliferation, angiogenesis, Alzheimer&#39;s disease, lung disease and osteoarthritis), the modulation of cellular events mediated by Wnt pathway signaling, as well as genetic diseases and neurological conditions/disorders/diseases due to mutations or dysregulation of the Wnt pathway and/or of one or more of Wnt signaling components. Also provided are methods for treating Wnt-related disease states.

RELATED APPLICATIONS Cross-Reference to Related Applications

This application is a continuation application of U.S. application Ser.No. 14/621,195, filed Feb. 12, 2015, which is a continuation applicationof U.S. application Ser. No. 14/178,749, filed Feb. 12, 2014, which is acontinuation application of U.S. application Ser. No. 13/800,963, filedMar. 13, 2013, which claims the benefit of U.S. Provisional ApplicationNo. 61/620,107, filed Apr. 4, 2012, all of which are incorporated hereinby reference in their entirety.

BACKGROUND OF THE INVENTION

Field of the Invention

This invention relates to inhibitors of one or more proteins in the Wntpathway, including inhibitors of one or more Wnt proteins, andcompositions comprising the same. More particularly, it concerns the useof an indazole compound or salts or analogs thereof, in the treatment ofdisorders characterized by the activation of Wnt pathway signaling(e.g., cancer, abnormal cellular proliferation, angiogenesis,Alzheimer's disease, lung disease and osteoarthritis), the modulation ofcellular events mediated by Wnt pathway signaling, as well as geneticdiseases and neurological conditions/disorders/diseases due to mutationsor dysregulation of the Wnt pathway and/or of one or more of Wntsignaling components. Also provided are methods for treating Wnt-relateddisease states.

Description of the Related Art

Pattern formation is the activity by which embryonic cells form orderedspatial arrangements of differentiated tissues. Speculation on themechanisms underlying these patterning effects usually centers on thesecretion of a signaling molecule that elicits an appropriate responsefrom the tissues being patterned. More recent work aimed at theidentification of such signaling molecules implicates secreted proteinsencoded by individual members of a small number of gene families.

A longstanding idea in cancer biology is that cancers arise and grow dueto the formation of cancer stem cells, which may constitute only aminority of the cells within a tumor but are nevertheless critical forits propagation. Stem cells are appealing as the cell of origin forcancer because of their pre-existing capacity for self-renewal and forunlimited replication. In addition, stem cells are relatively long-livedin comparison to other cells within tissues, providing a greateropportunity to accumulate the multiple additional mutations that may berequired to increase the rate of cell proliferation and produceclinically significant cancers. Of particular recent interest in theorigin of cancer is the observation that the Wnt signaling pathway,which has been implicated in stem cell self-renewal in normal tissues,upon continuous activation has also been associated with the initiationand growth of many types of cancer. This pathway thus provides apotential link between the normal self-renewal of stem cells and theaberrantly regulated proliferation of cancer stem cells.

The Wnt growth factor family includes more than 10 genes identified inthe mouse and at least 7 genes identified in the human. Members of theWnt family of signaling molecules mediate many important short- andlong-range patterning processes during invertebrate and vertebratedevelopment. The Wnt signaling pathway is known for its important rolein the inductive interactions that regulate growth and differentiation,and likely also plays important roles in the homeostatic maintenance ofpost-embryonic tissue integrity. Wnt stabilizes cytoplasmic p-catenin,which stimulates the expression of genes including c-myc, c jun, fra-1,and cyclin D1. In addition, misregulation of Wnt signaling can causedevelopmental defects and is implicated in the genesis of several humancancers. More recently, the Wnt pathway has been implicated in themaintenance of stem or progenitor cells in a growing list of adulttissues that now includes skin, blood, gut, prostate, muscle and thenervous system.

Pathological activation of the Wnt pathway is also believed to be theinitial event leading to colorectal cancer in over 85% of all sporadiccases in the Western world. Activation of the Wnt pathway has also beenextensively reported for hepatocellular carcinoma, breast cancer,ovarian cancer, pancreatic cancer, melanomas, mesotheliomas, lymphomasand leukemias. In addition to cancer, inhibitors of the Wnt pathway canbe used for stem cell research or for the treatment of any diseasescharacterized by aberrant Wnt activation such as diabetic retinopathy,pulmonary fibrosis, rheumatoid arthritis, scleroderma as well as mycoticand viral infections and bone and cartilage diseases. As such, it is atherapeutic target that is of great interest to the field.

In addition to cancer, there are many cases of genetic diseases due tomutations in Wnt signaling components. Examples of some of the manydiseases are Alzheimer's disease [Proc. Natl. Acad. Sci. USA (2007),104(22), 9434-9], osteoarthritis, polyposis coli [Science (1991),253(5020), 665-669], bone density and vascular defects in the eye(osteoporosis-pseudoglioma syndrome, OPPG) [N. Engl. J. Med. (2002),346(20), 1513-21], familial exudative vitreoretinopathy [Hum. Mutat.(2005), 26(2), 104-12], retinal angiogenesis [Nat. Genet. (2002), 32(2),326-30], early coronary disease [Science (2007), 315(5816), 1278-82],tetra-amelia syndrome [Am. J. Hum. Genet. (2004), 74(3), 558-63],Müllerian-duct regression and virilization [Engl. J. Med. (2004),351(8), 792-8], SERKAL syndrome [Am. J. Hum. Genet. (2008), 82(1),39-47], diabetes mellitus type 2 [Am. J. Hum. Genet. (2004), 75(5),832-43; N. Engl. J. Med. (2006), 355(3), 241-50], Fuhrmann syndrome [Am.J. Hum. Genet. (2006), 79(2), 402-8], Al-Awadi/Raas-Rothschild/Schinzelphocomelia syndrome [Am. J. Hum. Genet. (2006), 79(2), 402-8],odonto-onycho-dermal dysplasia [Am. J. Hum. Genet. (2007), 81(4),821-8], obesity [Diabetologia (2006), 49(4), 678-84], split-hand/footmalformation [Hum. Mol. Genet. (2008), 17(17), 2644-53], caudalduplication syndrome [Am. J. Hum. Genet. (2006), 79(1), 155-62], toothagenesis [Am. J. Hum. Genet. (2004), 74(5), 1043-50], Wilms tumor[Science (2007), 315(5812), 642-5], skeletal dysplasia [Nat. Genet.(2009), 41(1), 95-100], focal dermal hypoplasia [Nat. Genet. (2007),39(7), 836-8], autosomal recessive anonychia [Nat. Genet. (2006),38(11), 1245-7], neural tube defects [N. Engl. J. Med. (2007), 356(14),1432-7], alpha-thalassemia (ATRX) syndrome [The Journal of Neuroscience(2008), 28(47), 12570-12580], fragile X syndrome [PLoS Genetics (2010),6(4), e1000898], ICF syndrome, Angelman syndrome [Brain ResearchBulletin (2002), 57(1), 109-119], Prader-Willi syndrome [Journal ofNeuroscience (2006), 26(20), 5383-5392], Beckwith-Wiedemann Syndrome[Pediatric and Developmental Pathology (2003), 6(4), 299-306] and Rettsyndrome.

Regulation of cell signaling by the Wnt signaling pathway is criticalfor the formation of neuronal circuits. Wnt pathway modulates in neuraltissue, among other things, axon pathfinding, dendritic development, andsynaptic assembly. Through different receptors, Wnt pathway activatesand/or regulates diverse signaling pathways and other processes thatlead to local changes on the cytoskeleton or global cellular changesinvolving nuclear function. Recently, a link between neuronal activity,essential for the formation and refinement of neuronal connections, andWnt signaling has been uncovered. Indeed, neuronal activity regulatesthe release of various Wnt proteins and the localization of theirreceptors. Wnt pathway mediates synaptic structural changes induced byneuronal activity or experience. Evidence suggests that dysfunction inWnt signaling contributes to neurological disorders [Brain ResearchReviews (2000), 33(1), 1-12; Oncogene (2006) 25(57), 7545-7553;Molecular Neurodegeneration (2008), 3, 9; Neurobiology of Disease(2010), 38(2), 148-153; Journal of Neurodevelopmental Disorders (2011),3(2), 162-174 and Cold Spring Harbor Perspectives in Biology February(2012), 4(2)].

SUMMARY OF THE INVENTION

The present invention makes available methods and reagents, involvingcontacting a cell with an agent, such as an aromatic compound, in asufficient amount to antagonize a Wnt activity, e. g., to reverse orcontrol an aberrant growth state or correct a genetic disorder due tomutations in Wnt signaling components.

Some embodiments disclosed herein include Wnt inhibitors containing anindazole core. Other embodiments disclosed herein include pharmaceuticalcompositions and methods of treatment using these compounds.

One embodiment disclosed herein includes a compound having the structureof Formula I:

as well as prodrugs and pharmaceutically acceptable salts thereof.

In some embodiments of Formula (I):

R¹ is -heteroarylR³R⁴;

R² is selected from the group consisting of H, -heteroarylR⁵,-heterocyclylR⁶ and -arylR⁷;

R³ is selected from the group consisting of H, -heterocyclylR⁸,—NHC(═O)R⁹, —NHSO₂R¹⁰, —NR¹¹R¹² and —(C₁₋₆ alkyl)NR¹¹R¹²;

with the proviso that R² and R³ are not both H;

R⁴ is 1-3 substituents each selected from the group consisting of H,C₁₋₉ alkyl, halide, —CF₃, —CN, OR¹³ and amino;

each R⁵ is independently 1-4 substituents each selected from the groupconsisting of H, C₁₋₉ alkyl, halide, —CF₃, —CN, OR¹³, —C(═O)R¹¹, aminoand —(C₁₋₆ alkyl)NR¹¹R¹²;

each R⁶ is independently 1-5 substituents each selected from the groupconsisting of H, C₁₋₉ alkyl, halide, —CF₃, —CN, OR¹³ and amino;

each R⁷ is independently 1-5 substituents each selected from the groupconsisting of H, C₁₋₉ alkyl, halide, —CF₃, —CN, OR¹³, amino, —(C₁₋₆alkyl)NHSO₂R¹¹, —NR¹²(C₁₋₆ alkyl)NR¹¹R¹² and —(C₁₋₆ alkyl)NR¹¹R¹²;

R⁸ is 1-5 substituents each selected from the group consisting of H,C₁₋₉ alkyl, halide, —CF₃, —CN, OR¹³ and amino;

R⁹ is selected from the group consisting of C₁₋₉ alkyl, -heteroarylR⁵,-heterocyclylR⁶, -arylR⁷ and —CH₂carbocyclyl;

R¹⁰ is selected from the group consisting of C₁₋₉ alkyl, -heteroarylR⁵,-heterocyclylR⁶, -arylR⁷, and -carbocyclylR¹⁴;

each R¹¹ is independently selected from C₁₋₆ alkyl;

each R¹² is independently selected from the group consisting of H andC₁₋₆ alkyl;

each R¹¹ and R¹² are optionally linked to form a five or six memberedheterocyclyl ring;

each R¹³ is independently selected from the group consisting of H andC₁₋₆ alkyl;

R¹⁴ is 1-5 substituents each selected from the group consisting of H,C₁₋₉ alkyl, halide, —CF₃, —CN, OR¹³ and amino;

with the proviso that Formula I is not a structure selected from thegroup consisting of:

Some embodiments include stereoisomers and pharmaceutically acceptablesalts of a compound of general Formula (I).

Some embodiments include pro-drugs of a compound of general Formula (I).

Some embodiments of the present invention include pharmaceuticalcompositions comprising a compound of general Formula (I) and apharmaceutically acceptable carrier.

Other embodiments disclosed herein include methods of inhibiting one ormore members of the Wnt pathway, including one or more Wnt proteins byadministering to a subject affected by a disorder or disease in whichaberrant Wnt signaling is implicated, such as cancer and other diseasesassociated with abnormal angiogenesis, cellular proliferation, cellcycling and mutations in Wnt signaling components, a compound accordingto any of the above formulas. Accordingly, the compounds andcompositions provided herein can be used to treat cancer, to reduce orinhibit angiogenesis, to reduce or inhibit cellular proliferation andcorrect an genetic disorder due to mutations in Wnt signalingcomponents. Non-limiting examples of diseases which can be treated withthe compounds and compositions provided herein include a variety ofcancers, diabetic retinopathy, pulmonary fibrosis, rheumatoid arthritis,scleroderma, mycotic and viral infections, osteochondrodysplasia,Alzheimer's disease, lung disease, osteoarthritis, polyposis coli,osteoporosis-pseudoglioma syndrome, familial exudativevitreoretinopathy, retinal angiogenesis, early coronary disease,tetra-amelia syndrome, Müllerian-duct regression and virilization,SERKAL syndrome, diabetes mellitus type 2, Fuhrmann syndrome,Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome,odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation,caudal duplication syndrome, tooth agenesis, Wilms tumor, skeletaldysplasia, focal dermal hypoplasia, autosomal recessive anonychia,neural tube defects, alpha-thalassemia (ATRX) syndrome, fragile Xsyndrome, ICF syndrome, Angelman syndrome, Prader-Willi syndrome,Beckwith-Wiedemann Syndrome and Rett syndrome.

Another embodiment disclosed herein includes a pharmaceuticalcomposition that has a compound according to any of the above formulasand a pharmaceutically acceptable carrier, diluent, or excipient.

Some embodiments of the present invention include methods to prepare acompound of general Formula (I).

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory onlyand are not restrictive of the invention, as claimed.

DETAILED DESCRIPTION OF THE INVENTION

Compositions and methods for inhibiting one or more members of the Wntpathway, including one or more Wnt proteins would be of tremendousbenefit. Certain embodiments provide such compositions and methods.Certain related compounds and methods are disclosed in U.S. applicationSer. No. 12/852,706, filed Aug. 9, 2010, which claims priority to U.S.Provisional Application Ser. Nos. 61/232,603 and 61/305,459, all ofwhich are incorporated by reference in their entirety herein.

Some embodiments relate to a method for treating a disease such ascancers, diabetic retinopathy, pulmonary fibrosis, rheumatoid arthritis,scleroderma, mycotic and viral infections, osteochondrodysplasia,Alzheimer's disease, lung disease, osteoarthritis, polyposis coli,osteoporosis-pseudoglioma syndrome, familial exudativevitreoretinopathy, retinal angiogenesis, early coronary disease,tetra-amelia syndrome, Müllerian-duct regression and virilization,SERKAL syndrome, diabetes mellitus type 2, Fuhrmann syndrome,Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome,odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation,caudal duplication syndrome, tooth agenesis, Wilms tumor, skeletaldysplasia, focal dermal hypoplasia, autosomal recessive anonychia,neural tube defects, alpha-thalassemia (ATRX) syndrome, fragile Xsyndrome, ICF syndrome, Angelman syndrome, Prader-Willi syndrome,Beckwith-Wiedemann Syndrome and Rett syndrome.

In some embodiments, pharmaceutical compositions are provided that areeffective for treatment of a disease of an animal, e.g., a mammal,caused by the pathological activation or mutations of the Wnt pathway.The composition includes a pharmaceutically acceptable carrier and a Wntpathway inhibitor as described herein.

Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of ordinary skillin the art to which this disclosure belongs. All patents, applications,published applications, and other publications are incorporated byreference in their entirety. In the event that there is a plurality ofdefinitions for a term herein, those in this section prevail unlessstated otherwise.

In this specification and in the claims, the following terms have themeanings as defined. As used herein, “alkyl” means a branched, orstraight chain chemical group containing only carbon and hydrogen, suchas methyl, ethyl, n-propyl isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, n-pentyl, tert-pentyl, neopentyl, isopentyl and sec-pentyl.Alkyl groups can either be unsubstituted or substituted with one or moresubstituents, e.g., halide, alkoxy, acyloxy, amino, amido, cyano, nitro,hydroxyl, thio, carboxy, carbonyl, benzyloxy, aryl, heteroaryl,heterocyclyl, carbocycyl, or other functionality that may be suitablyblocked, if necessary for purposes of the invention, with a protectinggroup. Alkyl groups can be saturated or unsaturated (e.g., containing—C═C— or —C≡C— subunits), at one or several positions. Typically, alkylgroups will comprise 1 to 9 carbon atoms, preferably 1 to 6, morepreferably 1 to 4, and most preferably 1 to 2 carbon atoms.

As used herein, “carbocyclyl” means a cyclic ring system containing onlycarbon atoms in the ring system backbone, such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, and cyclohexenyl. Carbocyclyls mayinclude multiple fused rings. Carbocyclyls may have any degree ofsaturation provided that at least one ring in the ring system is notaromatic. Carbocyclyl groups can either be unsubstituted or substitutedwith one or more substituents, e.g., alkyl, halide, alkoxy, acyloxy,amino, amido, cyano, nitro, hydroxyl, mercapto, carboxy, carbonyl,benzyloxy, aryl, heteroaryl, or other functionality that may be suitablyblocked, if necessary for purposes of the invention, with a protectinggroup. Typically, carbocyclyl groups will comprise 3 to 10 carbon atoms,preferably 3 to 6.

As used herein, “lower alkyl” means a subset of alkyl, and thus is ahydrocarbon substituent, which is linear, or branched. Preferred loweralkyls are of 1 to about 4 carbons, and may be branched or linear.Examples of lower alkyl include butyl, propyl, isopropyl, ethyl, andmethyl. Likewise, radicals using the terminology “lower” refer toradicals preferably with 1 to about 4 carbons in the alkyl portion ofthe radical.

As used herein, “amido” means a H—CON— or alkyl-CON—, carbocyclyl-CON—,aryl-CON—, heteroaryl-CON— or heterocyclyl-CON group wherein the alkyl,carbocyclyl, heteroaryl, aryl or heterocyclyl group is as hereindescribed.

As used herein, “aryl” means an aromatic radical having a single-ring(e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl)with only carbon atoms present in the ring backbone. Aryl groups caneither be unsubstituted or substituted with one or more substituents,e.g., amino, cyano, hydroxyl, lower alkyl, haloalkyl, alkoxy, nitro,halo, mercapto, and other substituents. A preferred carbocyclic aryl isphenyl.

As used herein, the term “heteroaryl” means an aromatic radical havingone or more heteroatom(s) (e.g., N, O, or S) in the ring backbone andmay include a single ring (e.g., pyridine) or multiple condensed rings(e.g., quinoline). Heteroaryl groups can either be unsubstituted orsubstituted with one or more substituents, e.g., amino, cyano, hydroxyl,lower alkyl, haloalkyl, alkoxy, nitro, halo, mercapto, and othersubstituents. Examples of heteroaryls include thienyl, pyridinyl, furyl,oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl,pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl,pyridazinyl, triazinyl, thiazolyl benzothienyl, benzoxadiazolyl,benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl,indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl,thienopyridinyl, pyrido[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyridinyl,quinazolinyl, quinolinyl, thieno[2,3-c]pyridinyl, pyrazolo[3,4-b]pyridinyl, pyrazolo [3,4-c]pyridinyl, pyrazolo [4,3-c]pyridine,pyrazolo[4,3-b]pyridinyl, tetrazolyl, and others.

In these definitions it is clearly contemplated that substitution on thearyl and heteroaryl rings is within the scope of certain embodiments.Where substitution occurs, the radical is called substituted aryl orsubstituted heteroaryl. Preferably one to three and more preferably oneor two substituents occur on the aryl ring. Though many substituentswill be useful, preferred substituents include those commonly found inaryl compounds, such as alkyl, carbocyclyl, hydroxy, alkoxy, cyano,halo, haloalkyl, mercapto and the like.

As used herein, “amide” includes both RNR′CO— and RCONR′—. R can besubstituted or unsubstituted alkyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted heteroaryl, substituted orunsubstituted aryl, or substituted or unsubstituted carbocyclyl. R′ canbe H or substituted or unsubstituted alkyl.

As used herein, “halo”, “halide” or “halogen” is a chloro, bromo, fluoroor iodo atom radical. Chloro, bromo and fluoro are preferred halides.Most preferred halide is fluorine.

As used herein, “haloalkyl” means a hydrocarbon substituent, which is alinear or branched or cyclic alkyl, alkenyl or alkynyl substituted withchloro, bromo, fluoro or iodo atom(s). Most preferred of these arefluoroalkyls, wherein one or more of the hydrogen atoms have beensubstituted by fluoro. Preferred haloalkyls are of 1 to about 3 carbonsin length, more preferred haloalkyls are 1 to about 2 carbons, and mostpreferred are 1 carbon in length. The skilled artisan will recognizethen that as used herein, “haloalkylene” means a diradical variant ofhaloalkyl, such diradicals may act as spacers between radicals, otheratoms, or between the parent ring and another functional group.

As used herein, “heterocyclyl” means a cyclic ring system comprising atleast one heteroatom in the ring system backbone. Heterocyclyls mayinclude multiple fused rings. Heterocyclyls may have any degree ofsaturation provided that at least one ring in the ring system is notaromatic. Heterocyclyls may be substituted or unsubstituted with one ormore substituents, e.g., alkyl, halide, alkoxy, acyloxy, amino, amido,cyano, nitro, hydroxyl, mercapto, carboxy, carbonyl, benzyloxy, aryl,heteroaryl, and other substituents, and are attached to other groups viaany available valence, preferably any available carbon or nitrogen. Morepreferred heterocycles are of 5-7 members. In six membered monocyclicheterocycles, the heteroatom(s) are selected from one up to three of O,N or S, and wherein when the heterocycle is five membered, preferably ithas one or two heteroatoms selected from O, N, or S. Examples ofheterocyclyl include azirinyl, aziridinyl, azetidinyl, oxetanyl,thietanyl, 1,4,2-dithiazolyl, 1,3-benzodioxolyl, dihydroisoindolyl,dihydroisoquinolinyl, dihydrocinnolinyl, dihydrobenzodioxinyl,dihydro[1,3]oxazolo[4,5-b]pyridinyl, benzothiazolyl, dihydroindolyl,dihydropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl,isoindolinyl, morpholinyl, thiomorpholinyl, piperazinyl, pyranyl,pyrrolidinyl, tetrahydrofuryl, tetrahydropyridinyl, oxazinyl, thiazinyl,thiinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl,piperidinyl, pyrazolidinyl imidazolidinyl, thiomorpholinyl, and others.

As used herein, “substituted amino” means an amino radical which issubstituted by one or two alkyl, carbocycyl, aryl, heteroaryl orheterocyclyl groups, wherein the alkyl, carbocyclyl, aryl, heteroaryl orheterocyclyl are defined as above.

As used herein, “substituted thiol” means RS— group wherein R is analkyl, an aryl, heteroaryl or a heterocyclyl group, wherein the alkyl,carbocyclyl, aryl, heteroaryl or heterocyclyl are defined as above.

As used herein, “sulfonyl” means an alkylSO₂, arylSO₂, heteroarylSO₂,carbocyclylSO₂, or heterocyclyl-SO₂ group wherein the alkyl,carbocyclyl, aryl, heteroaryl or heterocyclyl are defined as above.

As used herein, “sulfonamido” means an alkyl-S(O)₂N—, aryl-S(O)₂N—,heteroaryl-S(O)₂N—, carbocyclyl-S(O)₂N— or heterocyclyl-S(O)₂N— groupwherein the alkyl, carbocyclyl, aryl, heteroaryl or heterocyclyl groupis as herein described.

As used herein, when two groups are indicated to be “linked” or “bonded”to form a “ring,” it is to be understood that a bond is formed betweenthe two groups and may involve replacement of a hydrogen atom on one orboth groups with the bond, thereby forming a carbocyclyl, heterocyclyl,aryl, or heteroaryl ring. The skilled artisan will recognize that suchrings can and are readily formed by routine chemical reactions, and itis within the purview of the skilled artisan to both envision such ringsand the methods of their formations. Preferred are rings having from 3-7members, more preferably 5 or 6 members. As used herein the term “ring”or “rings” when formed by the combination of two radicals refers toheterocyclic, carbocyclic, aryl, or heteroaryl rings.

The skilled artisan will recognize that some structures described hereinmay be resonance forms or tautomers of compounds that may be fairlyrepresented by other chemical structures, even when kinetically; theartisan recognizes that such structures are only a very small portion ofa sample of such compound(s). Such compounds are clearly contemplatedwithin the scope of this invention, though such resonance forms ortautomers are not represented herein.

The compounds provided herein may encompass various stereochemicalforms. The compounds also encompasses diastereomers as well as opticalisomers, e.g. mixtures of enantiomers including racemic mixtures, aswell as individual enantiomers and diastereomers, which arise as aconsequence of structural asymmetry in certain compounds. Separation ofthe individual isomers or selective synthesis of the individual isomersis accomplished by application of various methods which are well knownto practitioners in the art. Unless otherwise indicated, when adisclosed compound is named or depicted by a structure withoutspecifying the stereochemistry and has one or more chiral centers, it isunderstood to represent all possible stereoisomers of the compound.

The term “administration” or “administering” refers to a method ofgiving a dosage of a compound or pharmaceutical composition to avertebrate or invertebrate, including a mammal, a bird, a fish, or anamphibian, where the method is, e.g., orally, subcutaneously,intravenously, intranasally, topically, transdermally,intraperitoneally, intramuscularly, intrapulmonarilly, vaginally,rectally, ontologically, neuro-otologically, intraocularly,subconjuctivally, via anterior eye chamber injection, intravitreally,intraperitoneally, intrathecally, intracystically, intrapleurally, viawound irrigation, intrabuccally, intra-abdominally, intra-articularly,intra-aurally, intrabronchially, intracapsularly, intrameningeally, viainhalation, via endotracheal or endobronchial instillation, via directinstillation into pulmonary cavities, intraspinally, intrasynovially,intrathoracically, via thoracostomy irrigation, epidurally,intratympanically, intracisternally, intravascularly,intraventricularly, intraosseously, via irrigation of infected bone, orvia application as part of any admixture with a prosthetic device. Thepreferred method of administration can vary depending on variousfactors, e.g., the components of the pharmaceutical composition, thesite of the disease, the disease involved, and the severity of thedisease.

A “diagnostic” as used herein is a compound, method, system, or devicethat assists in the identification and characterization of a health ordisease state. The diagnostic can be used in standard assays as is knownin the art.

The term “mammal” is used in its usual biological sense. Thus, itspecifically includes humans, cattle, horses, dogs, and cats, but alsoincludes many other species.

The term “pharmaceutically acceptable carrier” or “pharmaceuticallyacceptable excipient” includes any and all solvents, co-solvents,complexing agents, dispersion media, coatings, antibacterial andantifungal agents, isotonic and absorption delaying agents and the likewhich are not biologically or otherwise undesirable. The use of suchmedia and agents for pharmaceutically active substances is well known inthe art. Except insofar as any conventional media or agent isincompatible with the active ingredient, its use in the therapeuticcompositions is contemplated. Supplementary active ingredients can alsobe incorporated into the compositions. In addition, various adjuvantssuch as are commonly used in the art may be included. These and othersuch compounds are described in the literature, e.g., in the MerckIndex, Merck & Company, Rahway, N.J. Considerations for the inclusion ofvarious components in pharmaceutical compositions are described, e.g.,in Gilman et al. (Eds.) (2010); Goodman and Gilman's: ThePharmacological Basis of Therapeutics, 12th Ed., The McGraw-HillCompanies.

The term “pharmaceutically acceptable salt” refers to salts that retainthe biological effectiveness and properties of the compounds providedherein and, which are not biologically or otherwise undesirable. In manycases, the compounds provided herein are capable of forming acid and/orbase salts by virtue of the presence of amino and/or carboxyl groups orgroups similar thereto. Pharmaceutically acceptable acid addition saltscan be formed with inorganic acids and organic acids. Inorganic acidsfrom which salts can be derived include, for example, hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and thelike. Organic acids from which salts can be derived include, forexample, acetic acid, propionic acid, glycolic acid, pyruvic acid,oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid, and the like. Pharmaceutically acceptable base additionsalts can be formed with inorganic and organic bases. Inorganic basesfrom which salts can be derived include, for example, sodium, potassium,lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese,aluminum, and the like; particularly preferred are the ammonium,potassium, sodium, calcium and magnesium salts. Organic bases from whichsalts can be derived include, for example, primary, secondary, andtertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines, basic ion exchange resins, and thelike, specifically such as isopropylamine, trimethylamine, diethylamine,triethylamine, tripropylamine, and ethanolamine. Many such salts areknown in the art, as described in WO 87/05297.

“Solvate” refers to the compound formed by the interaction of a solventand a Wnt pathway inhibitor, a metabolite, or salt thereof. Suitablesolvates are pharmaceutically acceptable solvates including hydrates.

“Patient” as used herein, means a human or a non-human mammal, e.g., adog, a cat, a mouse, a rat, a cow, a sheep, a pig, a goat, a non-humanprimate or a bird, e.g., a chicken, as well as any other vertebrate orinvertebrate.

By “therapeutically effective amount” or “pharmaceutically effectiveamount” of a compound as provided herein is one which is sufficient toachieve the desired effect and may vary according to the nature andseverity of the disease condition, and the potency of the compound.“Therapeutically effective amount” is also intended to include one ormore of the compounds of Formula (I) in combination with one or moreother agents that are effective to inhibit Wnt related diseases and/orconditions. The combination of compounds is preferably a synergisticcombination. Synergy, as described, for example, by Chou, CancerResearch (2010), 70(2), 440-446, occurs when the effect of the compoundswhen administered in combination is greater than the additive effect ofthe compounds when administered alone as a single agent. In general, asynergistic effect is most clearly demonstrated at sub-optimalconcentrations of the compounds. It will be appreciated that differentconcentrations may be employed for prophylaxis than for treatment of anactive disease. This amount can further depend upon the patient'sheight, weight, sex, age and medical history.

A therapeutic effect relieves, to some extent, one or more of thesymptoms of the disease, and includes curing a disease. “Curing” meansthat the symptoms of active disease are eliminated. However, certainlong-term or permanent effects of the disease may exist even after acure is obtained (such as extensive tissue damage).

“Treat,” “treatment,” or “treating,” as used herein refers toadministering a compound or pharmaceutical composition as providedherein for therapeutic purposes. The term “therapeutic treatment” refersto administering treatment to a patient already suffering from a diseasethus causing a therapeutically beneficial effect, such as amelioratingexisting symptoms, preventing additional symptoms, ameliorating orpreventing the underlying metabolic causes of symptoms, postponing orpreventing the further development of a disorder and/or reducing theseverity of symptoms that will or are expected to develop.

“Drug-eluting” and or controlled release as used herein refers to anyand all mechanisms, e.g., diffusion, migration, permeation, and/ordesorption by which the drug(s) incorporated in the drug-elutingmaterial pass therefrom over time into the surrounding body tissue.

“Drug-eluting material” and or controlled release material as usedherein refers to any natural, synthetic or semi-synthetic materialcapable of acquiring and retaining a desired shape or configuration andinto which one or more drugs can be incorporated and from whichincorporated drug(s) are capable of eluting over time.

“Elutable drug” as used herein refers to any drug or combination ofdrugs having the ability to pass over time from the drug-elutingmaterial in which it is incorporated into the surrounding areas of thebody.

Compounds

The compounds and compositions described herein can be used asanti-proliferative agents, e.g., anti-cancer and anti-angiogenesisagents, and/or as inhibitors of the Wnt signaling pathway, e.g., fortreating diseases or disorders associated with aberrant Wnt signaling.In addition, the compounds can be used as inhibitors of one or morekinases, kinase receptors, or kinase complexes. Such compounds andcompositions are also useful for controlling cellular proliferation,differentiation, and/or apoptosis.

Some embodiments of the present invention include compounds, salts,pharmaceutically acceptable salts or pro-drug thereof of Formula (I):

In some embodiments, R¹ is -heteroarylR³R⁴.

In some embodiments, R² is selected from the group consisting of H,-heteroarylR⁵, -heterocyclylR⁶ and -arylR⁷.

In some embodiments, R³ is selected from the group consisting of H,-heterocyclylR⁸, —NHC(═O)R⁹, —NHSO₂R¹⁰, —NR¹¹R¹² and —(C₁₋₆alkyl)NR¹¹R¹².

In some embodiments, there is the proviso that R² and R³ are not both H.

In some embodiments, R⁴ is 1-3 substituents each selected from the groupconsisting of H, C₁₋₉ alkyl, halide, —CF₃, —CN, OR¹³ and amino.

In some embodiments, each R⁵ is independently 1-4 substituents eachselected from the group consisting of H, C₁₋₉ alkyl, halide, —CF₃, —CN,OR¹³, —C(═O)R¹¹, amino and —(C₁₋₆ alkyl)NR¹¹R¹².

In some embodiments, each R⁶ is independently 1-5 substituents eachselected from the group consisting of H, C₁₋₉ alkyl, halide, —CF₃, —CN,OR¹³ and amino.

In some embodiments, each R⁷ is independently 1-5 substituents eachselected from the group consisting of H, C₁₋₉ alkyl, halide, —CF₃, —CN,OR¹³, amino, —(C₁₋₆ alkyl)NHSO₂R¹¹, —NR¹²(C₁₋₆ alkyl)NR¹¹R¹² and —(C₁₋₆alkyl)NR¹¹R¹².

In some embodiments, R⁸ is 1-5 substituents each selected from the groupconsisting of H, C₁₋₉ alkyl, halide, —CF₃, —CN, OR¹³ and amino.

In some embodiments, R⁹ is selected from the group consisting of C₁₋₉alkyl, -heteroarylR⁵, -heterocyclylR⁶, -arylR⁷ and —CH₂carbocyclyl.

In some embodiments, R¹⁰ is selected from the group consisting of C₁₋₉alkyl, -heteroarylR⁵, -heterocyclylR⁶, -arylR⁷, and -carbocyclylR¹⁴.

In some embodiments, each R¹¹ is independently selected from C₁₋₆ alkyl.

In some embodiments, each R¹² is independently selected from the groupconsisting of H and C₁₋₆ alkyl.

In some embodiments, each R¹¹ and R¹² are optionally linked to form afive or six membered heterocyclyl ring.

In some embodiments, each R¹³ is independently selected from the groupconsisting of H and C₁₋₆ alkyl.

In some embodiments, R¹⁴ is 1-5 substituents each selected from thegroup consisting of H, C₁₋₉ alkyl, halide, —CF₃, —CN, OR¹³ and amino.

In some embodiments, there is the proviso that Formula I is not astructure selected from the group consisting of:

In some embodiments, R¹ is pyridineR³R⁴.

In some embodiments, R¹ is pyridin-3-ylR³R⁴.

In some embodiments, R³ is H.

In some embodiments, R³ is —(C₁₋₆ alkyl)NR¹¹R¹².

In some embodiments, R³ is —(C₁₋₄ alkyl)NR¹¹R¹².

In some embodiments, R³ is —(C₁₋₂ alkyl)NR¹¹R¹².

In some embodiments, R³ is —CH₂NR¹¹R¹².

In some embodiments, R³ is NR¹¹R¹².

In some embodiments, R¹¹ is —(C₁₋₂ alkyl).

In some embodiments, R¹² is —(C₁₋₂ alkyl).

In some embodiments, R¹² is H.

In some embodiments, R⁴ is H.

In some embodiments, R⁴ is amino.

In some embodiments, R¹¹ and R¹² are linked to form a five or sixmembered heterocyclyl ring.

In some embodiments, R¹¹ and R¹² are linked to form a morpholine ring.

In some embodiments, R¹¹ and R¹² are linked to form a piperidine ring.

In some embodiments, R¹¹ and R¹² are linked to form a pyrrolidine ring.

In some embodiments, R¹¹ and R¹² are linked to form a piperazine ring.

In some embodiments, R¹¹ and R¹² are linked to form

In some embodiments, R³ is —NHC(═O)R⁹.

In some embodiments, R⁹ is —(C₂₋₅ alkyl).

In some embodiments, R⁹ is phenyl.

In some embodiments, R⁹ is —CH₂carbocyclyl.

In some embodiments, R³ is —NHSO₂R¹⁰.

In some embodiments, R¹⁰ is —(C₁₋₄ alkyl).

In some embodiments, R¹⁰ is phenyl.

In some embodiments, R³ is -heterocyclylR⁸.

In some embodiments, R³ is morpholine.

In some embodiments, R³ is piperazine.

In some embodiments, R³ is piperidine

In some embodiments, R³ is 1-methylpiperazine.

In some embodiments, R² is -heteroarylR⁵.

In some embodiments, R² is -pyridinylR⁵.

In some embodiments, R² is -pyridin-2-ylR⁵.

In some embodiments, R² is -pyridin-3-ylR⁵.

In some embodiments, R² is -pyridin-4-ylR⁵.

In some embodiments, R⁵ is 1-2 fluorine atoms.

In some embodiments, R² is thiopheneR⁵.

In some embodiments, R² is furanR⁵.

In some embodiments, R² is imidazoleR⁵.

In some embodiments, R² is selected from the group consisting of:

In some embodiments, R² is -heterocyclylR⁶.

In some embodiments, R² is morpholine.

In some embodiments, R² is piperazine.

In some embodiments, R² is piperidine.

In some embodiments, R² is 1-methylpiperazine.

In some embodiments, R⁶ is selected from the group consisting of H, Fand —(C₁₋₄ alkyl).

In some embodiments, R² is -arylR⁷.

In some embodiments, R² is -phenylR⁷.

In some embodiments, R⁷ is 1-2 fluorine atoms.

In some embodiments, R⁷ is —(C₁₋₆ alkyl)NHSO₂R¹¹.

In some embodiments, R⁷ is —(C₁₋₄ alkyl)NHSO₂R¹¹.

In some embodiments, R⁷ is —(C₁₋₂ alkyl)NHSO₂R¹¹.

In some embodiments, R⁷ is —CH₂NHSO₂R¹¹.

In some embodiments, R⁷ is —CH₂NHSO₂CH₃.

In some embodiments, R⁷ is —NR¹²(C₁₋₆ alkyl)NR¹¹R¹².

In some embodiments, R⁷ is —NR¹²(C₁₋₄ alkyl)NR¹¹R¹².

In some embodiments, R⁷ is —NR¹²CH₂CH₂NR¹¹R¹².

In some embodiments, R⁷ is —NHCH₂CH₂NR¹¹R¹².

In some embodiments, R⁷ is —NHCH₂CH₂N(CH₃)₂.

In some embodiments, R⁷ is 2 substituents consisting of 1 fluorine atomand —NR¹²(C₁₋₆ alkyl)NR¹¹R¹².

In some embodiments, R⁷ is 2 substituents consisting of 1 fluorine atomand —NHCH₂CH₂NR¹¹R¹².

In some embodiments, R⁷ is 2 substituents consisting of 1 fluorine atomand —(C₁₋₆ alkyl)NHSO₂R¹¹.

In some embodiments, R⁷ is 2 substituents consisting of 1 fluorine atomand —CH₂NHSO₂R¹¹.

In some embodiments, R¹ is pyridin-3-ylR³R⁴; R³ is H; R⁴ is H; R² isselected from the group consisting of pyridine and -heterocyclylR⁶; andR⁶ is selected from the group consisting of H, F and —(C₁₋₄ alkyl).

In some embodiments, R¹ is pyridin-3-ylR³R⁴; R³ is H; R⁴ is amino; R² isselected from the group consisting of -heteroarylR⁵, -phenylR⁷ and-heterocyclylR⁶; R⁵ is H; R⁶ is selected from the group consisting of H,F and —(C₁₋₄ alkyl); R⁷ is 1-2 fluorine atoms; and the heteroaryl isselected from the group consisting of pyridine, furan and thiophene.

In some embodiments, R¹ is pyridin-3-ylR³R⁴; R³ is —NHC(═O)R⁹; R⁴ is H;R⁹ is selected from the group consisting of ethyl, propyl, isopropyl,butyl, isobutyl, tert-butyl, neopentyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and phenyl; R² is selected from the groupconsisting of H, -heteroarylR⁵, -phenylR⁷ and -heterocyclylR⁶; R⁵ is Hor F; R⁶ is selected from the group consisting of H, F and —(C₁₋₄alkyl); R⁷ is selected from the group consisting of 1-2 fluorine atomsand —CH₂NHSO₂R¹¹; and the heteroaryl is selected from the groupconsisting of pyridine, furan and thiophene.

In some embodiments, R¹ is pyridin-3-ylR³R⁴; R³ is —CH₂NR¹¹R¹²; R⁴ is H;R² is selected from the group consisting of H, -heteroarylR⁵, -phenylR⁷and -heterocyclylR⁶; R⁵ is selected from the group consisting of H, F,Me and —C(═O)Me; R⁶ is selected from the group consisting of H, F and—(C₁₋₄ alkyl); R⁷ is 1-2 fluorine atoms; R¹¹ and R¹² are linked to forma five-membered heterocyclyl ring; the heterocyclyl ring is substitutedwith 1-2 fluorine atoms; and the heteroaryl is selected from the groupconsisting of pyridine, furan and thiophene.

Illustrative compounds of Formula (I) are shown in Table 1.

TABLE 1  

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232

233

234

235

236

237

238

239

240

241

242

243

244

245

246

247

248

249

250

251

252

253

254

255

256

257

258

259

260

261

262

263

264

265

266

267

268

269

270

271

272

273

274

275

276

277

278

279

280

281

282

283

284

285

286

287

288

289

290

291

292

293

294

295

296

297

298

299

300

301

302

303

304

305

306

307

308

309

310

311

312

313

314

315

316

317

318

319

320

321

322

323

324

325

326

327

328

329

330

331

332

333

334

335

336

337

338

339

340

341

342

343

344

345

346

347

348

349

350

351

352

353

354

355

356

357

358

359

360

361

362

363

364

365

366

367

368

369

370

371

372

373

374

375

376

377

378

379

380

381

382

383

384

385

386

387

388

389

390

391

392

393

394

395

396

397

398

399

400

401

402

403

404

405

406

407

408

409

410

411

412

413

414

415

416

417

418

419

420

421

422

423

424

425

426

427

428

429

430

431

432

433

434

435

436

437

438

439

440

441

442

443

444

445

446

447

448

449

450

451

452

453

454

455

456

457

458

459

460

461

462

463

464

465

466

467

468

469

470

471

472

273

474

475

476

477

478

479

480

481

482

483

484

485

486

487

488

489

490

491

492

493

494

495

496

497Administration and Pharmaceutical Compositions

Some embodiments include pharmaceutical compositions comprising: (a) asafe and therapeutically effective amount of the indazole, or itscorresponding enantiomer, diastereoisomer or tautomer, orpharmaceutically acceptable salt; and (b) a pharmaceutically acceptablecarrier.

The compounds provided herein may also be useful in combination(administered together or sequentially) with other known agents.

Non-limiting examples of diseases which can be treated with acombination of a compound of Formula (I) and other known agents arecolorectal cancer, ovarian cancer, retinitis pigmentosa, maculardegeneration, idiopathic pulmonary fibrosis and osteoarthritis.

In some embodiments, colorectal cancer can be treated with a combinationof a compound of either Formula (I) and one or more of the followingdrugs: 5-Fluorouracil (5-FU), which is often given with the vitamin-likedrug leucovorin (also called folinic acid); Capecitabine (Xeloda®),Irinotecan (Camptosar®), Oxaliplatin (Eloxatin®). Examples ofcombinations of these drugs which could be further combined with acompound of either Formula (I) are FOLFOX (5-FU, leucovorin, andoxaliplatin), FOLFIRI (5-FU, leucovorin, and irinotecan), FOLFOXIRI(leucovorin, 5-FU, oxaliplatin, and irinotecan) and CapeOx (Capecitabineand oxaliplatin). For rectal cancer, chemo with 5-FU or capecitabinecombined with radiation may be given before surgery (neoadjuvanttreatment).

In some embodiments, ovarian cancer can be treated with a combination ofa compound of either Formula (I) and one or more of the following drugs:Topotecan, Liposomal doxorubicin (Doxil®), Gemcitabine (Gemzar®),Cyclophosphamide (Cytoxan®), Vinorelbine (Navelbine®), Ifosfamide(Ifex®), Etoposide (VP-16), Altretamine (Hexalen®), Capecitabine(Xeloda®), Irinotecan (CPT-11, Camptosar®), Melphalan, Pemetrexed(Alimta®) and Albumin bound paclitaxel (nab-paclitaxel, Abraxane®).Examples of combinations of these drugs which could be further combinedwith a compound of either Formula (I) are TIP (paclitaxel [Taxol],ifosfamide, and cisplatin), VeIP (vinblastine, ifosfamide, andcisplatin) and VIP (etoposide [VP-16], ifosfamide, and cisplatin).

In some embodiments, a compound of either Formula (I) can be used totreat cancer in combination with any of the following methods: (a)Hormone therapy such as aromatase inhibitors, LHRH [luteinizinghormone-releasing hormone] analogs and inhibitors, and others; (b)Ablation or embolization procedures such as radiofrequency ablation(RFA), ethanol (alcohol) ablation, microwave thermotherapy andcryosurgery (cryotherapy); (c) Chemotherapy using alkylating agents suchas cisplatin and carboplatin, oxaliplatin, mechlorethamine,cyclophosphamide, chlorambucil and ifosfamide; (d) Chemotherapy usinganti-metabolites such as azathioprine and mercaptopurine; (e)Chemotherapy using plant alkaloids and terpenoids such as vincaalkaloids (i.e. Vincristine, Vinblastine, Vinorelbine and Vindesine) andtaxanes; (f) Chemotherapy using podophyllotoxin, etoposide, teniposideand docetaxel; (g) Chemotherapy using topoisomerase inhibitors such asirinotecan, topotecan, amsacrine, etoposide, etoposide phosphate, andteniposide; (h) Chemotherapy using cytotoxic antibiotics such asactinomycin, anthracyclines, doxorubicin, daunorubicin, valrubicin,idarubicin, epirubicin, bleomycin, plicamycin and mitomycin; (i)Chemotherapy using tyrosine-kinase inhibitors such as Imatinib mesylate(Gleevec®, also known as STI-571), Gefitinib (Iressa, also known asZD1839), Erlotinib (marketed as Tarceva®), Bortezomib (Velcade®),tamoxifen, tofacitinib, crizotinib, Bcl-2 inhibitors (e.g. obatoclax inclinical trials, ABT-263, and Gossypol), PARP inhibitors (e.g. Iniparib,Olaparib in clinical trials), PI3K inhibitors (eg. perifosine in a phaseIII trial), VEGF Receptor 2 inhibitors (e.g. Apatinib), AN-152,(AEZS-108), Braf inhibitors (e.g. vemurafenib, dabrafenib and LGX818),MEK inhibitors (e.g. trametinib and MEK162), CDK inhibitors, (e.g.PD-0332991), salinomycin and Sorafenib; (j) Chemotherapy usingmonoclonal antibodies such as Rituximab (marketed as MabThera® orRituxan®), Trastuzumab (Herceptin also known as ErbB2), Cetuximab(marketed as Erbitux®) and Bevacizumab (marketed as Avastin®); and (k)radiation therapy.

In some embodiments, idiopathic pulmonary fibrosis can be treated with acombination of a compound of either Formula (I) and one or more of thefollowing drugs: pirfenidone (pirfenidone was approved for use in 2011in Europe under the brand name Esbriet®), prednisone, azathioprine,N-acetylcysteine, interferon-γ 1b, bosentan (bosentan is currently beingstudied in patients with IPF, [The American Journal of Respiratory andCritical Care Medicine (2011), 184(1), 92-9]), Nintedanib (BIBF 1120 andVargatef), QAX576 [British Journal of Pharmacology (2011), 163(1),141-172], and anti-inflammatory agents such as corticosteroids.

In some embodiments, a compound of either Formula (I) can be used totreat idiopathic pulmonary fibrosis in combination with any of thefollowing methods: oxygen therapy, pulmonary rehabilitation and surgery.

In some embodiments, a compound of either Formula (I) can be used totreat osteoarthritis in combination with any of the following methods:(a) Nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen,naproxen, aspirin and acetaminophen; (b) physical therapy; (c)injections of corticosteroid medications; (d) injections of hyaluronicacid derivatives (e.g. Hyalgan, Synvisc); (e) narcotics, like codeine;(f) in combination with braces and/or shoe inserts or any device thatcan immobilize or support your joint to help you keep pressure off it(e.g., splints, braces, shoe inserts or other medical devices); (g)realigning bones (osteotomy); (h) joint replacement (arthroplasty); and(i) in combination with a chronic pain class.

In some embodiments, macular degeneration can be treated with acombination of a compound of either Formula (I) and one or more of thefollowing drugs: Bevacizumab (Avastin®), Ranibizumab (Lucentis®),Pegaptanib (Macugen), Aflibercept (Eylea®), verteporfin (Visudyne®) incombination with photodynamic therapy (PDT) or with any of the followingmethods: (a) in combination with laser to destroy abnormal blood vessels(photocoagulation); and (b) in combination with increased vitamin intakeof antioxidant vitamins and zinc.

In some embodiments, retinitis pigmentosa can be treated with acombination of a compound of either Formula (I) and one or more of thefollowing drugs: UF-021 (Ocuseva™), vitamin A palmitate and pikachurinor with any of the following methods: (a) with the Argus® II retinalimplant; and (b) with stem cell and/or gene therapy.

Administration of the compounds disclosed herein or the pharmaceuticallyacceptable salts thereof can be via any of the accepted modes ofadministration for agents that serve similar utilities including, butnot limited to, orally, subcutaneously, intravenously, intranasally,topically, transdermally, intraperitoneally, intramuscularly,intrapulmonarilly, vaginally, rectally, ontologically,neuro-otologically, intraocularly, subconjuctivally, via anterior eyechamber injection, intravitreally, intraperitoneally, intrathecally,intracystically, intrapleurally, via wound irrigation, intrabuccally,intra-abdominally, intra-articularly, intra-aurally, intrabronchially,intravascularly, intrameningeally, via inhalation, via endotracheal orendobronchial instillation, via direct instillation into pulmonarycavities, intraspinally, intrasynovially, intrathoracically, viathoracostomy irrigation, epidurally, intratympanically,intracisternally, intravascularly, intraventricularly, intraosseously,via irrigation of infected bone, or via application as part of anyadmixture with a prosthetic devices. Oral and parenteral administrationsare customary in treating the indications.

Compounds provided herein intended for pharmaceutical use may beadministered as crystalline or amorphous products. Pharmaceuticallyacceptable compositions may include solid, semi-solid, liquid,solutions, colloidal, liposomes, emulsions, suspensions, complexes,coacervates and aerosols. Dosage forms, such as, e.g., tablets,capsules, powders, liquids, suspensions, suppositories, aerosols,implants, controlled release or the like. They may be obtained, forexample, as solid plugs, powders, or films by methods such asprecipitation, crystallization, milling, grinding, supercritical fluidprocessing, coacervation, complex coacervation, encapsulation,emulsification, complexation, freeze drying, spray drying, orevaporative drying. Microwave or radio frequency drying may be used forthis purpose. The compounds can also be administered in sustained orcontrolled release dosage forms, including depot injections, osmoticpumps, pills (tablets and or capsules), transdermal (includingelectrotransport) patches, implants and the like, for prolonged and/ortimed, pulsed administration at a predetermined rate.

The compounds can be administered either alone or more typically incombination with a conventional pharmaceutical carrier, excipient or thelike. The term “excipient” is used herein to describe any ingredientother than the compound(s) provided herein. Pharmaceutically acceptableexcipients include, but are not limited to, ion exchangers, alumina,aluminum stearate, lecithin, self-emulsifying drug delivery systems(SEDDS) such as d-α-tocopherol polyethylene glycol 1000 succinate,surfactants used in pharmaceutical dosage forms such as Tweens,poloxamers or other similar polymeric delivery matrices, serum proteins,such as human serum albumin, buffer substances such as phosphates, tris,glycine, sorbic acid, potassium sorbate, partial glyceride mixtures ofsaturated vegetable fatty acids, water, salts or electrolytes, such asprotamine sulfate, disodium hydrogen phosphate, potassium hydrogenphosphate, sodium-chloride, zinc salts, colloidal silica, magnesiumtrisilicate, polyvinyl pyrrolidone, cellulose-based substances,polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates,waxes, polyethylene-polyoxypropylene-block polymers, and wool fat.Cyclodextrins such as α-, β, and γ-cyclodextrin, or chemically modifiedderivatives such as hydroxyalkylcyclodextrins, including 2- and3-hydroxypropyl-b-cyclodextrins, or other solubilized derivatives canalso be advantageously used to enhance delivery of compounds describedherein. Dosage forms or compositions containing a compound as describedherein in the range of 0.005% to 100% with the balance made up fromnontoxic carrier may be prepared. The contemplated compositions maycontain 0.001%-100% active ingredient, in one embodiment 0.1-95%, inanother embodiment 75-85%, in a further embodiment 20-80%, Actualmethods of preparing such dosage forms are known, or will be apparent,to those skilled in this art; for example, see Remington: The Scienceand Practice of Pharmacy, 22^(nd) Edition (Pharmaceutical Press, London,UK. 2012).

In one preferred embodiment, the compositions will take the form of aunit dosage form such as a pill or tablet and thus the composition maycontain, along with the active ingredient, a diluent such as lactose,sucrose, dicalcium phosphate, or the like; a lubricant such as magnesiumstearate or the like; and a binder such as starch, gum acacia,polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or thelike. In another solid dosage form, a powder, marume, solution orsuspension (e.g., in propylene carbonate, vegetable oils, PEG's,poloxamer 124 or triglycerides) is encapsulated in a capsule (gelatin orcellulose base capsule). Unit dosage forms in which the two activeingredients are physically separated are also contemplated; e.g.,capsules with granules (or tablets in a capsule) of each drug; two-layertablets; two-compartment gel caps, etc. Enteric coated or delayedrelease oral dosage forms are also contemplated.

Liquid pharmaceutically administrable compositions can, for example, beprepared by dissolving, dispersing, etc. an active compound as definedabove and optional pharmaceutical adjuvants in a carrier (e.g., water,saline, aqueous dextrose, glycerol, glycols, ethanol or the like) toform a solution, colloid, liposome, emulsion, complexes, coacervate orsuspension. If desired, the pharmaceutical composition can also containminor amounts of nontoxic auxiliary substances such as wetting agents,emulsifying agents, co-solvents, solubilizing agents, pH bufferingagents and the like (e.g., sodium acetate, sodium citrate, cyclodextrinederivatives, sorbitan monolaurate, triethanolamine acetate,triethanolamine oleate, and the like).

In some embodiments, the unit dosage of compounds of Formula (I) is 0.25mg/Kg to 50 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) is 0.25mg/Kg to 20 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) is 0.50mg/Kg to 19 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) is 0.75mg/Kg to 18 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) is 1.0mg/Kg to 17 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) is 1.25mg/Kg to 16 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) is 1.50mg/Kg to 15 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) is 1.75mg/Kg to 14 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) is 2.0mg/Kg to 13 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) is 3.0mg/Kg to 12 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) is 4.0mg/Kg to 11 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) is 5.0mg/Kg to 10 mg/Kg in humans.

In some embodiments, the compositions are provided in unit dosage formssuitable for single administration of a precise dose.

In some embodiments, the compositions are provided in unit dosage formssuitable for twice a day administration of a precise dose.

In some embodiments, the compositions are provided in unit dosage formssuitable for three times a day administration of a precise dose.

Injectables can be prepared in conventional forms, either as liquidsolutions, colloid, liposomes, complexes, coacervate or suspensions, asemulsions, or in solid forms suitable for reconstitution in liquid priorto injection. The percentage of active compound contained in suchparenteral compositions is highly dependent on the specific naturethereof, as well as the activity of the compound and the needs of thesubject. However, percentages of active ingredient of 0.01% to 10% insolution are employable, and could be higher if the composition is asolid or suspension, which could be subsequently diluted to the abovepercentages.

In some embodiments, the composition will comprise 0.1-10% of the activeagent in solution.

In some embodiments, the composition will comprise 0.1-5% of the activeagent in solution.

In some embodiments, the composition will comprise 0.1-4% of the activeagent in solution.

In some embodiments, the composition will comprise 0.15-3% of the activeagent in solution.

In some embodiments, the composition will comprise 0.2-2% of the activeagent in solution.

In some embodiments, the compositions are provided in dosage formssuitable for continuous dosage by intravenous infusion over a period of1-96 hours.

In some embodiments, the compositions are provided in dosage formssuitable for continuous dosage by intravenous infusion over a period of1-72 hours.

In some embodiments, the compositions are provided in dosage formssuitable for continuous dosage by intravenous infusion over a period of1-48 hours.

In some embodiments, the compositions are provided in dosage formssuitable for continuous dosage by intravenous infusion over a period of1-24 hours.

In some embodiments, the compositions are provided in dosage formssuitable for continuous dosage by intravenous infusion over a period of1-12 hours.

In some embodiments, the compositions are provided in dosage formssuitable for continuous dosage by intravenous infusion over a period of1-6 hours.

In some embodiments, these compositions can be administered byintravenous infusion to humans at doses of 5 mg/m² to 300 mg/m².

In some embodiments, these compositions can be administered byintravenous infusion to humans at doses of 5 mg/m² to 200 mg/m².

In some embodiments, these compositions can be administered byintravenous infusion to humans at doses of 5 mg/m² to 100 mg/m².

In some embodiments, these compositions can be administered byintravenous infusion to humans at doses of 10 mg/m² to 50 mg/m².

In some embodiments, these compositions can be administered byintravenous infusion to humans at doses of 50 mg/m² to 200 mg/m².

In some embodiments, these compositions can be administered byintravenous infusion to humans at doses of 75 mg/m² to 175 mg/m².

In some embodiments, these compositions can be administered byintravenous infusion to humans at doses of 100 mg/m² to 150 mg/m².

It is to be noted that concentrations and dosage values may also varydepending on the specific compound and the severity of the condition tobe alleviated. It is to be further understood that for any particularpatient, specific dosage regimens should be adjusted over time accordingto the individual need and the professional judgment of the personadministering or supervising the administration of the compositions, andthat the concentration ranges set forth herein are exemplary only andare not intended to limit the scope or practice of the claimedcompositions.

In one preferred embodiment, the compositions can be administered to therespiratory tract (including nasal and pulmonary) e.g., through anebulizer, metered-dose inhalers, atomizer, mister, aerosol, dry powderinhaler, insufflator, liquid instillation or other suitable device ortechnique.

In some embodiments, aerosols intended for delivery to the nasal mucosaare provided for inhalation through the nose. For optimal delivery tothe nasal cavities, inhaled particle sizes of about 5 to about 100microns are useful, with particle sizes of about 10 to about 60 micronsbeing preferred. For nasal delivery, a larger inhaled particle size isdesired to maximize impaction on the nasal mucosa and to minimize orprevent pulmonary deposition of the administered formulation. In someembodiments, aerosols intended for delivery to the lung are provided forinhalation through the nose or the mouth. For optimal delivery to thelung, inhaled aerodynamic particle sizes of about less than 10 μm areuseful, with an aerodynamic particle size of about 1 to about 10 micronsbeing preferred Inhaled particles may be defined as liquid dropletscontaining dissolved drug, liquid droplets containing suspended drugparticles (in cases where the drug is insoluble in the suspendingmedium), dry particles of pure drug substance, drug substanceincorporated with excipients, liposomes, emulsions, colloidal systems,coacervates, aggregates of drug nanoparticles, or dry particles of adiluent which contain embedded drug nanoparticles.

In some embodiments, compounds of Formula (I) disclosed herein intendedfor respiratory delivery (either systemic or local) can be administeredas aqueous formulations, as non-aqueous solutions or suspensions, assuspensions or solutions in halogenated hydrocarbon propellants with orwithout alcohol, as a colloidal system, as emulsions, coacervates or asdry powders. Aqueous formulations may be aerosolized by liquidnebulizers employing either hydraulic or ultrasonic atomization or bymodified micropump systems (like the soft mist inhalers, the Aerodose®or the AERx® systems). Propellant-based systems may use suitablepressurized metered-dose inhalers (pMDIs). Dry powders may use drypowder inhaler devices (DPIs), which are capable of dispersing the drugsubstance effectively. A desired particle size and distribution may beobtained by choosing an appropriate device.

In some embodiments, the compositions of Formula (I) disclosed hereincan be administered to the ear by various methods. For example, a roundwindow catheter (e.g., U.S. Pat. Nos. 6,440,102 and 6,648,873) can beused.

Alternatively, formulations can be incorporated into a wick for usebetween the outer and middle ear (e.g., U.S. Pat. No. 6,120,484) orabsorbed to collagen sponge or other solid support (e.g., U.S. Pat. No.4,164,559).

If desired, formulations of the invention can be incorporated into a gelformulation (e.g., U.S. Pat. Nos. 4,474,752 and 6,911,211).

In some embodiments, compounds of Formula (I) disclosed herein intendedfor delivery to the ear can be administered via an implanted pump anddelivery system through a needle directly into the middle or inner ear(cochlea) or through a cochlear implant stylet electrode channel oralternative prepared drug delivery channel such as but not limited to aneedle through temporal bone into the cochlea.

Other options include delivery via a pump through a thin film coatedonto a multichannel electrode or electrode with a specially imbeddeddrug delivery channel (pathways) carved into the thin film for thispurpose. In other embodiments the acidic or basic solid compound ofFormula I can be delivered from the reservoir of an external or internalimplanted pumping system.

Formulations of the invention also can be administered to the ear byintratympanic injection into the middle ear, inner ear, or cochlea(e.g., U.S. Pat. No. 6,377,849 and Ser. No. 11/337,815).

Intratympanic injection of therapeutic agents is the technique ofinjecting a therapeutic agent behind the tympanic membrane into themiddle and/or inner ear. In one embodiment, the formulations describedherein are administered directly onto the round window membrane viatranstympanic injection. In another embodiment, the ion channelmodulating agent auris-acceptable formulations described herein areadministered onto the round window membrane via a non-transtympanicapproach to the inner ear. In additional embodiments, the formulationdescribed herein is administered onto the round window membrane via asurgical approach to the round window membrane comprising modificationof the crista fenestrae cochleae.

In some embodiments, the compounds of Formula (I) are formulated inrectal compositions such as enemas, rectal gels, rectal foams, rectalaerosols, suppositories, jelly suppositories, or retention enemas,containing conventional suppository bases such as cocoa butter or otherglycerides, as well as synthetic polymers such as polyvinylpyrrolidone,PEG (like PEG ointments), and the like.

Suppositories for rectal administration of the drug (either as asolution, colloid, suspension or a complex) can be prepared by mixingthe drug with a suitable non-irritating excipient that is solid atordinary temperatures but liquid at the rectal temperature and willtherefore melt or erode/dissolve in the rectum and release the drug.Such materials include cocoa butter, glycerinated gelatin, hydrogenatedvegetable oils, poloxamers, mixtures of polyethylene glycols of variousmolecular weights and fatty acid esters of polyethylene glycol. Insuppository forms of the compositions, a low-melting wax such as, butnot limited to, a mixture of fatty acid glycerides, optionally incombination with cocoa butter is first melted.

Solid compositions can be provided in various different types of dosageforms, depending on the physicochemical properties of the drug, thedesired dissolution rate, cost considerations, and other criteria. Inone of the embodiments, the solid composition is a single unit. Thisimplies that one unit dose of the drug is comprised in a single,physically shaped solid form or article. In other words, the solidcomposition is coherent, which is in contrast to a multiple unit dosageform, in which the units are incoherent.

Examples of single units which may be used as dosage forms for the solidcomposition include tablets, such as compressed tablets, film-likeunits, foil-like units, wafers, lyophilized matrix units, and the like.In a preferred embodiment, the solid composition is a highly porouslyophilized form. Such lyophilizates, sometimes also called wafers orlyophilized tablets, are particularly useful for their rapiddisintegration, which also enables the rapid dissolution of the activecompound.

On the other hand, for some applications the solid composition may alsobe formed as a multiple unit dosage form as defined above. Examples ofmultiple units are powders, granules, microparticles, pellets,mini-tablets, beads, lyophilized powders, and the like. In oneembodiment, the solid composition is a lyophilized powder. Such adispersed lyophilized system comprises a multitude of powder particles,and due to the lyophilization process used in the formation of thepowder, each particle has an irregular, porous microstructure throughwhich the powder is capable of absorbing water very rapidly, resultingin quick dissolution. Effervescent compositions are also contemplated toaid the quick dispersion and absorption of the compound.

Another type of multiparticulate system which is also capable ofachieving rapid drug dissolution is that of powders, granules, orpellets from water-soluble excipients which are coated with the drug, sothat the drug is located at the outer surface of the individualparticles. In this type of system, the water-soluble low molecularweight excipient is useful for preparing the cores of such coatedparticles, which can be subsequently coated with a coating compositioncomprising the drug and, preferably, one or more additional excipients,such as a binder, a pore former, a saccharide, a sugar alcohol, afilm-forming polymer, a plasticizer, or other excipients used inpharmaceutical coating compositions.

Also provided herein are kits. Typically, a kit includes one or morecompounds or compositions as described herein. In certain embodiments, akit can include one or more delivery systems, e.g., for delivering oradministering a compound as provided herein, and directions for use ofthe kit (e.g., instructions for treating a patient). In anotherembodiment, the kit can include a compound or composition as describedherein and a label that indicates that the contents are to beadministered to a patient with cancer. In another embodiment, the kitcan include a compound or composition as described herein and a labelthat indicates that the contents are to be administered to a patientwith one or more of hepatocellular carcinoma, colon cancer, leukemia,lymphoma, sarcoma, ovarian cancer, diabetic retinopathy, pulmonaryfibrosis, rheumatoid arthritis, scleroderma, mycotic and viralinfections, bone and cartilage diseases, Alzheimer's disease, lungdisease, osteoarthritis, polyposis coli, bone density and vasculardefects in the eye (Osteoporosis-pseudoglioma Syndrome, OPPG), familialexudative vitreoretinopathy, retinal angiogenesis, early coronarydisease, tetra-amelia, Müllerian-duct regression and virilization,SERKAL syndrome, type II diabetes, Fuhrmann syndrome,Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome,odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation,caudal duplication, tooth agenesis, Wilms tumor, skeletal dysplasia,focal dermal hypoplasia, autosomal recessive anonychia, neural tubedefects, alpha-thalassemia (ATRX) syndrome, fragile X syndrome, ICFsyndrome, Angelman's syndrome, Prader-Willi syndrome, Beckwith-WiedemannSyndrome, Norrie disease and Rett syndrome. The actual dose of theactive compounds of the present invention depends on the specificcompound, and on the condition to be treated; the selection of theappropriate dose is well within the knowledge of the skilled artisan.

Methods of Treatment

The compounds and compositions provided herein can be used as inhibitorsand/or modulators of one or more components of the Wnt pathway, whichmay include one or more Wnt proteins, and thus can be used to treat avariety of disorders and diseases in which aberrant Wnt signaling isimplicated, such as cancer and other diseases associated with abnormalangiogenesis, cellular proliferation, and cell cycling. Accordingly, thecompounds and compositions provided herein can be used to treat cancer,to reduce or inhibit angiogenesis, to reduce or inhibit cellularproliferation, to correct a genetic disorder, and/or to treat aneurological condition/disorder/disease due to mutations ordysregulation of the Wnt pathway and/or of one or more of Wnt signalingcomponents. Non-limiting examples of diseases which can be treated withthe compounds and compositions provided herein include a variety ofcancers, diabetic retinopathy, pulmonary fibrosis, rheumatoid arthritis,scleroderma, mycotic and viral infections, bone and cartilage diseases,neurological conditions/diseases such as Alzheimer's disease,amyotrophic lateral sclerosis (ALS), motor neurone disease, multiplesclerosis or autism, lung disease, osteoarthritis, polyposis coli, bonedensity and vascular defects in the eye (Osteoporosis-pseudogliomaSyndrome, OPPG), familial exudative vitreoretinopathy, retinalangiogenesis, early coronary disease, tetra-amelia, Müllerian-ductregression and virilization, SERKAL syndrome, type II diabetes, Fuhrmannsyndrome, Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome,odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation,caudal duplication, tooth agenesis, Wilms tumor, skeletal dysplasia,focal dermal hypoplasia, autosomal recessive anonychia, neural tubedefects, alpha-thalassemia (ATRX) syndrome, fragile X syndrome, ICFsyndrome, Angelman's syndrome, Prader-Willi syndrome, Beckwith-WiedemannSyndrome, Norrie disease and Rett syndrome.

With respect to cancer, the Wnt pathway is known to be constitutivelyactivated in a variety of cancers including, for example, colon cancer,hepatocellular carcinoma, lung cancer, ovarian cancer, prostate cancer,pancreatic cancer and leukemias such as CML, CLL and T-ALL. Theconstitutive activation is due to constitutively active β-catenin,perhaps due to its stabilization by interacting factors or inhibition ofthe degradation pathway. Accordingly, the compounds and compositionsdescribed herein may be used to treat these cancers in which the Wntpathway is constitutively activated. In certain embodiments, the canceris chosen from hepatocellular carcinoma, colon cancer, leukemia,lymphoma, sarcoma and ovarian cancer.

Other cancers can also be treated with the compounds and compositionsdescribed herein.

More particularly, cancers that may be treated by the compound,compositions and methods described herein include, but are not limitedto, the following:

1) Breast cancers, including, for example ER⁺ breast cancer, ER⁻ breastcancer, her2⁻ breast cancer, her2⁺ breast cancer, stromal tumors such asfibroadenomas, phyllodes tumors, and sarcomas, and epithelial tumorssuch as large duct papillomas; carcinomas of the breast including insitu (noninvasive) carcinoma that includes ductal carcinoma in situ(including Paget's disease) and lobular carcinoma in situ, and invasive(infiltrating) carcinoma including, but not limited to, invasive ductalcarcinoma, invasive lobular carcinoma, medullary carcinoma, colloid(mucinous) carcinoma, tubular carcinoma, and invasive papillarycarcinoma; and miscellaneous malignant neoplasms. Further examples ofbreast cancers can include luminal A, luminal B, basal A, basal B, andtriple negative breast cancer, which is estrogen receptor negative(ER⁻), progesterone receptor negative, and her2 negative (her2⁻). Insome embodiments, the breast cancer may have a high risk Oncotype score.

2) Cardiac cancers, including, for example sarcoma, e.g., angiosarcoma,fibrosarcoma, rhabdomyosarcoma, and liposarcoma; myxoma; rhabdomyoma;fibroma; lipoma and teratoma.

3) Lung cancers, including, for example, bronchogenic carcinoma, e.g.,squamous cell, undifferentiated small cell, undifferentiated large cell,and adenocarcinoma; alveolar and bronchiolar carcinoma; bronchialadenoma; sarcoma; lymphoma; chondromatous hamartoma; and mesothelioma.

4) Gastrointestinal cancer, including, for example, cancers of theesophagus, e.g., squamous cell carcinoma, adenocarcinoma,leiomyosarcoma, and lymphoma; cancers of the stomach, e.g., carcinoma,lymphoma, and leiomyosarcoma; cancers of the pancreas, e.g., ductaladenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors,and vipoma; cancers of the small bowel, e.g., adenocarcinoma, lymphoma,carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma,neurofibroma, and fibroma; cancers of the large bowel, e.g.,adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, andleiomyoma.)

) Genitourinary tract cancers, including, for example, cancers of thekidney, e.g., adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma,and leukemia; cancers of the bladder and urethra, e.g., squamous cellcarcinoma, transitional cell carcinoma, and adenocarcinoma; cancers ofthe prostate, e.g., adenocarcinoma, and sarcoma; cancer of the testis,e.g., seminoma, teratoma, embryonal carcinoma, teratocarcinoma,choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma,fibroadenoma, adenomatoid tumors, and lipoma.

6) Liver cancers, including, for example, hepatoma, e.g., hepatocellularcarcinoma; cholangiocarcinoma; hepatoblastoma; angiosarcoma;hepatocellular adenoma; and hemangioma.

7) Bone cancers, including, for example, osteogenic sarcoma(osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma,chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cellsarcoma), multiple myeloma, malignant giant cell tumor chordoma,osteochrondroma (osteocartilaginous exostoses), benign chondroma,chondroblastoma, chondromyxofibroma, osteoid osteoma and giant celltumors.

8) Nervous system cancers, including, for example, cancers of the skull,e.g., osteoma, hemangioma, granuloma, xanthoma, and osteitis deformans;cancers of the meninges, e.g., meningioma, meningiosarcoma, andgliomatosis; cancers of the brain, e.g., astrocytoma, medulloblastoma,glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform,oligodendroglioma, schwannoma, retinoblastoma, and congenital tumors;and cancers of the spinal cord, e.g., neurofibroma, meningioma, glioma,and sarcoma.

9) Gynecological cancers, including, for example, cancers of the uterus,e.g., endometrial carcinoma; cancers of the cervix, e.g., cervicalcarcinoma, and pre tumor cervical dysplasia; cancers of the ovaries,e.g., ovarian carcinoma, including serous cystadenocarcinoma, mucinouscystadenocarcinoma, unclassified carcinoma, granulosa theca cell tumors,Sertoli Leydig cell tumors, dysgerminoma, and malignant teratoma;cancers of the vulva, e.g., squamous cell carcinoma, intraepithelialcarcinoma, adenocarcinoma, fibrosarcoma, and melanoma; cancers of thevagina, e.g., clear cell carcinoma, squamous cell carcinoma, botryoidsarcoma, and embryonal rhabdomyosarcoma; and cancers of the fallopiantubes, e.g., carcinoma.

10) Hematologic cancers, including, for example, cancers of the blood,e.g., acute myeloid leukemia, chronic myeloid leukemia, acutelymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferativediseases, multiple myeloma, and myelodysplastic syndrome, Hodgkin'slymphoma, non-Hodgkin's lymphoma (malignant lymphoma) and Waldenstrom'smacroglobulinemia.

11) Skin cancers and skin disorders, including, for example, malignantmelanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi'ssarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma,keloids, and scleroderma.

12) Adrenal gland cancers, including, for example, neuroblastoma.

Cancers may be solid tumors that may or may not be metastatic. Cancersmay also occur, as in leukemia, as a diffuse tissue. Thus, the term“tumor cell,” as provided herein, includes a cell afflicted by any oneof the above identified disorders.

A method of treating cancer using a compound or composition as describedherein may be combined with existing methods of treating cancers, forexample by chemotherapy, irradiation, or surgery (e.g., oophorectomy).In some embodiments, a compound or composition can be administeredbefore, during, or after another anticancer agent or treatment.

The compounds and compositions described herein can be used asanti-angiogenesis agents and as agents for modulating and/or inhibitingthe activity of protein kinases, thus providing treatments for cancerand other diseases associated with cellular proliferation mediated byprotein kinases. For example, the compounds described herein can inhibitthe activity of one or more kinases. Accordingly, provided herein is amethod of treating cancer or preventing or reducing angiogenesis throughkinase inhibition.

In addition, and including treatment of cancer, the compounds andcompositions described herein can function as cell-cycle control agentsfor treating proliferative disorders in a patient. Disorders associatedwith excessive proliferation include, for example, cancers, scleroderma,immunological disorders involving undesired proliferation of leukocytes,and restenosis and other smooth muscle disorders. Furthermore, suchcompounds may be used to prevent de-differentiation of post-mitotictissue and/or cells.

Diseases or disorders associated with uncontrolled or abnormal cellularproliferation include, but are not limited to, the following:

-   -   a variety of cancers, including, but not limited to, carcinoma,        hematopoietic tumors of lymphoid lineage, hematopoietic tumors        of myeloid lineage, tumors of mesenchymal origin, tumors of the        central and peripheral nervous system and other tumors including        melanoma, seminoma and Kaposi's sarcoma.    -   a disease process which features abnormal cellular        proliferation, e.g., benign prostatic hyperplasia, familial        adenomatosis polyposis, neurofibromatosis, atherosclerosis,        arthritis, glomerulonephritis, restenosis following angioplasty        or vascular surgery, inflammatory bowel disease, transplantation        rejection, endotoxic shock, and fungal infections. Fibrotic        disorders such as skin fibrosis; scleroderma; progressive        systemic fibrosis; lung fibrosis; muscle fibrosis; kidney        fibrosis; glomerulosclerosis; glomerulonephritis; hypertrophic        scar formation; uterine fibrosis; renal fibrosis; cirrhosis of        the liver, liver fibrosis; adhesions, such as those occurring in        the abdomen, pelvis, spine or tendons; chronic obstructive        pulmonary disease; fibrosis following myocardial infarction;        pulmonary fibrosis; fibrosis and scarring associated with        diffuse/interstitial lung disease; central nervous system        fibrosis, such as fibrosis following stroke; fibrosis associated        with neuro-degenerative disorders such as Alzheimer's Disease or        multiple sclerosis; fibrosis associated with proliferative        vitreoretinopathy (PVR); restenosis; endometriosis; ischemic        disease and radiation fibrosis.    -   defective apoptosis-associated conditions, such as cancers        (including but not limited to those types mentioned herein),        viral infections (including but not limited to herpesvirus,        poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus),        prevention of AIDS development in HIV-infected individuals,        autoimmune diseases (including but not limited to systemic lupus        erythematosus, rheumatoid arthritis, scleroderma, autoimmune        mediated glomerulonephritis, inflammatory bowel disease and        autoimmune diabetes mellitus), neurodegenerative disorders        (including but not limited to Alzheimer's disease, lung disease,        amyotrophic lateral sclerosis, retinitis pigmentosa, Parkinson's        disease, AIDS-related dementia, spinal muscular atrophy and        cerebellar degeneration), myelodysplastic syndromes, aplastic        anemia, ischemic injury associated with myocardial infarctions,        stroke and reperfusion injury, arrhythmia, atherosclerosis,        toxin-induced or alcohol related liver diseases, hematological        diseases (including but not limited to chronic anemia and        aplastic anemia), degenerative diseases of the musculoskeletal        system (including but not limited to osteroporosis and        arthritis), aspirin-sensitive rhinosinusitis, cystic fibrosis,        multiple sclerosis, kidney diseases and cancer pain.    -   genetic diseases due to mutations in Wnt signaling components,        such as polyposis coli, osteoporosis-pseudoglioma syndrome,        familial exudative vitreoretinopathy, retinal angiogenesis,        early coronary disease, tetra-amelia syndrome, Müllerian-duct        regression and virilization, SERKAL syndrome, diabetes mellitus        type 2, Fuhrmann syndrome, Al-Awadi/Raas-Rothschild/Schinzel        phocomelia syndrome, odonto-onycho-dermal dysplasia, obesity,        split-hand/foot malformation, caudal duplication syndrome, tooth        agenesis, Wilms tumor, skeletal dysplasia, focal dermal        hypoplasia, autosomal recessive anonychia, neural tube defects,        alpha-thalassemia (ATRX) syndrome, fragile X syndrome, ICF        syndrome, Angelman syndrome, Prader-Willi syndrome,        Beckwith-Wiedemann Syndrome and Rett syndrome.

Furthermore, the compounds and compositions described herein can be usedto treat neurological conditions, disorders and/or diseases caused bydysfunction in the Wnt signaling pathway. Non-limiting examples ofneurological conditions/disorders/diseases which can be treated with thecompounds and compositions provided herein include Alzheimer's disease,aphasia, apraxia, arachnoiditis, ataxia telangiectasia, attentiondeficit hyperactivity disorder, auditory processing disorder, autism,alcoholism, Bell's palsy, bipolar disorder, brachial plexus injury,Canavan disease, carpal tunnel syndrome, causalgia, central painsyndrome, central pontine myelinolysis, centronuclear myopathy, cephalicdisorder, cerebral aneurysm, cerebral arteriosclerosis, cerebralatrophy, cerebral gigantism, cerebral palsy, cerebral vasculitis,cervical spinal stenosis, Charcot-Marie-Tooth disease, Chiarimalformation, chronic fatigue syndrome, chronic inflammatorydemyelinating polyneuropathy (CIDP), chronic pain, Coffin-Lowrysyndrome, complex regional pain syndrome, compression neuropathy,congenital facial diplegia, corticobasal degeneration, cranialarteritis, craniosynostosis, Creutzfeldt-Jakob disease, cumulativetrauma disorder, Cushing's syndrome, cytomegalic inclusion body disease(CIBD), Dandy-Walker syndrome, Dawson disease, De Morsier's syndrome,Dejerine-Klumpke palsy, Dejerine-Sottas disease, delayed sleep phasesyndrome, dementia, dermatomyositis, developmental dyspraxia, diabeticneuropathy, diffuse sclerosis, Dravet syndrome, dysautonomia,dyscalculia, dysgraphia, dyslexia, dystonia, empty sella syndrome,encephalitis, encephalocele, encephalotrigeminal angiomatosis,encopresis, epilepsy, Erb's palsy, erythromelalgia, essential tremor,Fabry's disease, Fahr's syndrome, familial spastic paralysis, febrileseizure, Fisher syndrome, Friedreich's ataxia, fibromyalgia, Foville'ssyndrome, Gaucher's disease, Gerstmann's syndrome, giant cell arteritis,giant cell inclusion disease, globoid cell leukodystrophy, gray matterheterotopia, Guillain-Barré syndrome, HTLV-1 associated myelopathy,Hallervorden-Spatz disease, hemifacial spasm, hereditary spasticparaplegia, heredopathia atactica polyneuritiformis, herpes zosteroticus, herpes zoster, Hirayama syndrome, holoprosencephaly,Huntington's disease, hydranencephaly, hydrocephalus, hypercortisolism,hypoxia, immune-mediated encephalomyelitis, inclusion body myositis,incontinentia pigmenti, infantile phytanic acid storage disease,infantile Refsum disease, infantile spasms, inflammatory myopathy,intracranial cyst, intracranial hypertension, Joubert syndrome, Karaksyndrome, Kearns-Sayre syndrome, Kennedy disease, Kinsbourne syndrome,Klippel Feil syndrome, Krabbe disease, Kugelberg-Welander disease, kuru,Lafora disease, Lambert-Eaton myasthenic syndrome, Landau-Kleffnersyndrome, lateral medullary (Wallenberg) syndrome, Leigh's disease,Lennox-Gastaut syndrome, Lesch-Nyhan syndrome, leukodystrophy, Lewy bodydementia, lissencephaly, locked-in syndrome, Lou Gehrig's disease,lumbar disc disease, lumbar spinal stenosis, Lyme disease,Machado-Joseph disease (Spinocerebellar ataxia type 3), macrencephaly,macropsia, megalencephaly, Melkersson-Rosenthal syndrome, Menieresdisease, meningitis, Menkes disease, etachromatic leukodystrophy,microcephaly, micropsia, Miller Fisher syndrome, misophonia,mitochondrial myopathy, Mobius syndrome, monomelic amyotrophy, motorneurone disease, motor skills disorder, Moyamoya disease,mucopolysaccharidoses, multi-infarct dementia, multifocal motorneuropathy, multiple sclerosis, multiple system atrophy, musculardystrophy, myalgic encephalomyelitis, myasthenia gravis, myelinoclasticdiffuse sclerosis, myoclonic Encephalopathy of infants, myoclonus,myopathy, myotubular myopathy, myotonia congenital, narcolepsy,neurofibromatosis, neuroleptic malignant syndrome, lupus erythematosus,neuromyotonia, neuronal ceroid lipofuscinosis, Niemann-Pick disease,O'Sullivan-McLeod syndrome, occipital Neuralgia, occult SpinalDysraphism Sequence, Ohtahara syndrome, olivopontocerebellar atrophy,opsoclonus myoclonus syndrome, optic neuritis, orthostatic hypotension,palinopsia, paresthesia, Parkinson's disease, paramyotonia Congenita,paraneoplastic diseases, paroxysmal attacks, Parry-Romberg syndrome,Pelizaeus-Merzbacher disease, periodic paralyses, peripheral neuropathy,photic sneeze reflex, phytanic acid storage disease, Pick's disease,polymicrogyria (PMG), polymyositis, porencephaly, post-polio syndrome,postherpetic neuralgia (PHN), postural hypotension, Prader-Willisyndrome, primary lateral sclerosis, prion diseases, progressivehemifacial atrophy, progressive multifocal leukoencephalopathy,progressive supranuclear palsy, pseudotumor cerebri, Ramsay Huntsyndrome type I, Ramsay Hunt syndrome type II, Ramsay Hunt syndrome typeIII, Rasmussen's encephalitis, reflex neurovascular dystrophy, Refsumdisease, restless legs syndrome, retrovirus-associated myelopathy, Rettsyndrome, Reye's syndrome, rhythmic movement disorder, Romberg syndrome,Saint Vitus dance, Sandhoff disease, schizophrenia, Schilder's disease,schizencephaly, sensory integration dysfunction, septo-optic dysplasia,Shy-Drager syndrome, Sjögren's syndrome, snatiation, Sotos syndrome,spasticity, spina bifida, spinal cord tumors, spinal muscular atrophy,spinocerebellar ataxia, Steele-Richardson-Olszewski syndrome,Stiff-person syndrome, stroke, Sturge-Weber syndrome, subacutesclerosing panencephalitis, subcortical arteriosclerotic encephalopathy,superficial siderosis, Sydenham's chorea, syncope, synesthesia,syringomyelia, tarsal tunnel syndrome, tardive dyskinesia, tardivedysphrenia, Tarlov cyst, Tay-Sachs disease, temporal arteritis, tetanus,tethered spinal cord syndrome, Thomsen disease, thoracic outletsyndrome, tic douloureux, Todd's paralysis, Tourette syndrome, toxicencephalopathy, transient ischemic attack, transmissible spongiformencephalopathies, transverse myelitis, tremor, trigeminal neuralgia,tropical spastic paraparesis, trypanosomiasis, tuberous sclerosis,ubisiosis, Von Hippel-Lindau disease (VHL), Viliuisk Encephalomyelitis(VE), Wallenberg's syndrome, Werdnig, Hoffman disease, west syndrome,Williams syndrome, Wilson's disease and Zellweger syndrome.

The compounds and compositions may also be useful in the inhibition ofthe development of invasive cancer, tumor angiogenesis and metastasis.

In some embodiments, the disclosure provides a method for treating adisease or disorder associated with aberrant cellular proliferation byadministering to a patient in need of such treatment an effective amountof one or more of the compounds of Formula (I), in combination(simultaneously or sequentially) with at least one other agent.

In some embodiments, the pharmaceutical composition comprises atherapeutically effective amount of a compound of Formula (I), or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient.

In some embodiments, the method of treats a disorder or disease in whichaberrant Wnt signaling is implicated in a patient, the method comprisesadministering to the patient a therapeutically effective amount of acompound of Formula (I), or a pharmaceutically acceptable salt thereof.

In some embodiments, the disorder or disease is cancer.

In some embodiments, the disorder or disease is diabetic retinopathy.

In some embodiments, the disorder or disease is pulmonary fibrosis.

In some embodiments, the disorder or disease is rheumatoid arthritis.

In some embodiments, the disorder or disease is scleroderma.

In some embodiments, the disorder or disease is a mycotic or viralinfection.

In some embodiments, the disorder or disease is a bone or cartilagedisease.

In some embodiments, the disorder or disease is Alzheimer's disease.

In some embodiments, the disorder or disease is osteoarthritis.

In some embodiments, the disorder or disease is lung disease

In some embodiments, the disorder or disease is a genetic disease causedby mutations in Wnt signaling components, wherein the genetic disease isselected from: polyposis coli, osteoporosis-pseudoglioma syndrome,familial exudative vitreoretinopathy, retinal angiogenesis, earlycoronary disease, tetra-amelia syndrome, Müllerian-duct regression andvirilization, SERKAL syndrome, diabetes mellitus type 2, Fuhrmannsyndrome, Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome,odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation,caudal duplication syndrome, tooth agenesis, Wilms tumor, skeletaldysplasia, focal dermal hypoplasia, autosomal recessive anonychia,neural tube defects, alpha-thalassemia (ATRX) syndrome, fragile Xsyndrome, ICF syndrome, Angelman syndrome, Prader-Willi syndrome,Beckwith-Wiedemann Syndrome, Norrie disease and Rett syndrome.

In some embodiments, the patient is a human.

In some embodiments, the cancer is chosen from: hepatocellularcarcinoma, colon cancer, breast cancer, pancreatic cancer, chronicmyeloid leukemia (CML), chronic myelomonocytic leukemia, chroniclymphocytic leukemia (CLL), acute myeloid leukemia, acute lymphocyticleukemia, Hodgkin lymphoma, lymphoma, sarcoma and ovarian cancer.

In some embodiments, the cancer is chosen from: lung cancer—non-smallcell, lung cancer—small cell, multiple myeloma, nasopharyngeal cancer,neuroblastoma, osteosarcoma, penile cancer, pituitary tumors, prostatecancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skincancer—basal and squamous cell, skin cancer—melanoma, small intestinecancer, stomach cancers, testicular cancer, thymus cancer, thyroidcancer, uterine sarcoma, vaginal cancer, vulvar cancer, laryngeal orhypopharyngeal cancer, kidney cancer, Kaposi sarcoma, gestationaltrophoblastic disease, gastrointestinal stromal tumor, gastrointestinalcarcinoid tumor, gallbladder cancer, eye cancer (melanoma and lymphoma),Ewing tumor, esophagus cancer, endometrial cancer, colorectal cancer,cervical cancer, brain or spinal cord tumor, bone metastasis, bonecancer, bladder cancer, bile duct cancer, anal cancer and adrenalcortical cancer.

In some embodiments, the cancer is hepatocellular carcinoma.

In some embodiments, the cancer is colon cancer.

In some embodiments, the cancer is breast cancer.

In some embodiments, the cancer is pancreatic cancer.

In some embodiments, the cancer is chronic myeloid leukemia (CML).

In some embodiments, the cancer is chronic myelomonocytic leukemia.

In some embodiments, the cancer is chronic lymphocytic leukemia (CLL).

In some embodiments, the cancer is acute myeloid leukemia.

In some embodiments, the cancer is acute lymphocytic leukemia.

In some embodiments, the cancer is Hodgkin lymphoma.

In some embodiments, the cancer is lymphoma.

In some embodiments, the cancer is sarcoma.

In some embodiments, the cancer is ovarian cancer.

In some embodiments, the cancer is lung cancer—non-small cell.

In some embodiments, the cancer is lung cancer—small cell.

In some embodiments, the cancer is multiple myeloma.

In some embodiments, the cancer is nasopharyngeal cancer.

In some embodiments, the cancer is neuroblastoma.

In some embodiments, the cancer is osteosarcoma.

In some embodiments, the cancer is penile cancer.

In some embodiments, the cancer is pituitary tumors.

In some embodiments, the cancer is prostate cancer.

In some embodiments, the cancer is retinoblastoma.

In some embodiments, the cancer is rhabdomyosarcoma.

In some embodiments, the cancer is salivary gland cancer.

In some embodiments, the cancer is skin cancer—basal and squamous cell.

In some embodiments, the cancer is skin cancer—melanoma.

In some embodiments, the cancer is small intestine cancer.

In some embodiments, the cancer is stomach cancers.

In some embodiments, the cancer is testicular cancer.

In some embodiments, the cancer is thymus cancer.

In some embodiments, the cancer is thyroid cancer.

In some embodiments, the cancer is uterine sarcoma.

In some embodiments, the cancer is vaginal cancer.

In some embodiments, the cancer is vulvar cancer.

In some embodiments, the cancer is Wilms tumor.

In some embodiments, the cancer is laryngeal or hypopharyngeal cancer.

In some embodiments, the cancer is kidney cancer.

In some embodiments, the cancer is Kaposi sarcoma.

In some embodiments, the cancer is gestational trophoblastic disease.

In some embodiments, the cancer is gastrointestinal stromal tumor.

In some embodiments, the cancer is gastrointestinal carcinoid tumor.

In some embodiments, the cancer is gallbladder cancer.

In some embodiments, the cancer is eye cancer (melanoma and lymphoma).

In some embodiments, the cancer is Ewing tumor.

In some embodiments, the cancer is esophagus cancer.

In some embodiments, the cancer is endometrial cancer.

In some embodiments, the cancer is colorectal cancer.

In some embodiments, the cancer is cervical cancer.

In some embodiments, the cancer is brain or spinal cord tumor.

In some embodiments, the cancer is bone metastasis.

In some embodiments, the cancer is bone cancer.

In some embodiments, the cancer is bladder cancer.

In some embodiments, the cancer is bile duct cancer.

In some embodiments, the cancer is anal cancer.

In some embodiments, the cancer is adrenal cortical cancer.

In some embodiments, the disorder or disease is a neurologicalcondition, disorder or disease, wherein the neurologicalcondition/disorder/disease is selected from: Alzheimer's disease,frontotemporal dementias, dementia with lewy bodies, prion diseases,Parkinson's disease, Huntington's disease, progressive supranuclearpalsy, corticobasal degeneration, mutiple system atrophy, amyotrophiclateral sclerosis (ALS), inclusion body myositis, autism, degenerativemyopathies, diabetic neuropathy, other metabolic neuropathies, endocrineneuropathies, orthostatic hypotension, multiple sclerosis andCharcot-Marie-Tooth disease.

In some embodiments, the compound of Formula (I) inhibits one or moreproteins in the Wnt pathway.

In some embodiments, the compound of Formula (I) inhibits signalinginduced by one or more Wnt proteins.

In some embodiments, the Wnt proteins are chosen from: WNT1, WNT2,WNT2B, WNT3, WNT3A, WNT4. WNT5A, WNT5B, WNT6, WNT7A, WNT7B, WNT8A,WNT8B, WNT9A, WNT9B, WNT10A, WNT10B, WNT11, and WNT16.

In some embodiments, the compound of Formula (I) inhibits a kinaseactivity.

In some embodiments, the method treats a disease or disorder mediated bythe Wnt pathway in a patient, the method comprises administering to thepatient a therapeutically effective amount of a compound (or compounds)of Formula (I), or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) inhibits one or moreWnt proteins.

In some embodiments, the method treats a disease or disorder mediated bykinase activity in a patient, the method comprises administering to thepatient a therapeutically effective amount of a compound (or compounds)of Formula (I), or a pharmaceutically acceptable salt thereof.

In some embodiments, the disease or disorder comprises tumor growth,cell proliferation, or angiogenesis.

In some embodiments, the method inhibits the activity of a proteinkinase receptor, the method comprises contacting the receptor with aneffective amount of a compound (or compounds) of Formula (I), or apharmaceutically acceptable salt thereof.

In some embodiments, the method treats a disease or disorder associatedwith aberrant cellular proliferation in a patient; the method comprisesadministering to the patient a therapeutically effective amount of acompound (or compounds) of Formula (I), or a pharmaceutically acceptablesalt thereof.

In some embodiments, the method prevents or reduces angiogenesis in apatient; the method comprises administering to the patient atherapeutically effective amount of a compound (or compounds) of Formula(I), or a pharmaceutically acceptable salt thereof.

In some embodiments, the method prevents or reduces abnormal cellularproliferation in a patient; the method comprises administering to thepatient a therapeutically effective amount of a compound (or compounds)of Formula (I), or a pharmaceutically acceptable salt thereof.

In some embodiments, the method treats a disease or disorder associatedwith aberrant cellular proliferation in a patient, the method comprisesadministering to the patient a pharmaceutical composition comprising oneor more of the compounds of claim 1 in combination with apharmaceutically acceptable carrier and one or more other agents.

Moreover, the compounds and compositions, for example, as inhibitors ofthe cyclin-dependent kinases (CDKs), can modulate the level of cellularRNA and DNA synthesis and therefore are expected to be useful in thetreatment of viral infections such as HIV, human papilloma virus, herpesvirus, Epstein-Barr virus, adenovirus, Sindbis virus, pox virus and thelike.

Compounds and compositions described herein can inhibit the kinaseactivity of, for example, CDK/cyclin complexes, such as those active inthe G₀. or G.₁ stage of the cell cycle, e.g., CDK2, CDK4, and/or CDK6complexes.

Evaluation of Biological Activity

The biological activity of the compounds described herein can be testedusing any suitable assay known to those of skill in the art, e.g., WO2001/053268 or WO 2005/009997. For example, the activity of a compoundmay be tested using one or more of the test methods outlined below.

In one example, tumor cells may be screened for Wnt independent growth.In such a method, tumor cells of interest are contacted with a compound(i.e. inhibitor) of interest, and the proliferation of the cells, e.g.by uptake of tritiated thymidine, is monitored. In some embodiments,tumor cells may be isolated from a candidate patient who has beenscreened for the presence of a cancer that is associated with a mutationin the Wnt signaling pathway. Candidate cancers include, withoutlimitation, those listed above.

In another example, one may utilize in vitro assays for Wnt biologicalactivity, e.g. stabilization of β-catenin and promoting growth of stemcells. Assays for biological activity of Wnt include stabilization ofβ-catenin, which can be measured, for example, by serial dilutions of acandidate inhibitor composition. An exemplary assay for Wnt biologicalactivity contacts a Wnt composition in the presence of a candidateinhibitor with cells, e.g. mouse L cells. The cells are cultured for aperiod of time sufficient to stabilize β-catenin, usually at least about1 hour, and lysed. The cell lysate is resolved by SDS PAGE, thentransferred to nitrocellulose and probed with antibodies specific forβ-catenin.

In a further example, the activity of a candidate compound can bemeasured in a Xenopus secondary axis bioassay (Leyns, L. et al. Cell(1997), 88(6), 747-756).

To further illustrate this invention, the following examples areincluded. The examples should not, of course, be construed asspecifically limiting the invention. Variations of these examples withinthe scope of the claims are within the purview of one skilled in the artand are considered to fall within the scope of the invention asdescribed, and claimed herein. The reader will recognize that theskilled artisan, armed with the present disclosure, and skill in the artis able to prepare and use the invention without exhaustive examples.

EXAMPLES Compound Preparation

The starting materials used in preparing the compounds of the inventionare known, made by known methods, or are commercially available. It willbe apparent to the skilled artisan that methods for preparing precursorsand functionality related to the compounds claimed herein are generallydescribed in the literature. The skilled artisan given the literatureand this disclosure is well equipped to prepare any of the compounds.

It is recognized that the skilled artisan in the art of organicchemistry can readily carry out manipulations without further direction,that is, it is well within the scope and practice of the skilled artisanto carry out these manipulations. These include reduction of carbonylcompounds to their corresponding alcohols, oxidations, acylations,aromatic substitutions, both electrophilic and nucleophilic,etherifications, esterification and saponification and the like. Thesemanipulations are discussed in standard texts such as March's AdvancedOrganic Chemistry: Reactions, Mechanisms, and Structure 7^(th) Ed., JohnWiley & Sons (2013), Carey and Sundberg, Advanced Organic Chemistry5^(th) Ed., Springer (2007), Comprehensive Organic Transformations: AGuide to Functional Group Transformations, 2^(nd) Ed., John Wiley & Sons(1999) (incorporated herein by reference in its entirety) and the like.

The skilled artisan will readily appreciate that certain reactions arebest carried out when other functionality is masked or protected in themolecule, thus avoiding any undesirable side reactions and/or increasingthe yield of the reaction. Often the skilled artisan utilizes protectinggroups to accomplish such increased yields or to avoid the undesiredreactions. These reactions are found in the literature and are also wellwithin the scope of the skilled artisan. Examples of many of thesemanipulations can be found for example in T. Greene and P. WutsProtective Groups in Organic Synthesis, 4th Ed., John Wiley & Sons(2007), incorporated herein by reference in its entirety.

Trademarks used herein are examples only and reflect illustrativematerials used at the time of the invention. The skilled artisan willrecognize that variations in lot, manufacturing processes, and the like,are expected. Hence the examples, and the trademarks used in them arenon-limiting, and they are not intended to be limiting, but are merelyan illustration of how a skilled artisan may choose to perform one ormore of the embodiments of the invention.

¹H nuclear magnetic resonance spectra (NMR) were measured in theindicated solvents on a Bruker NMR spectrometer (Avance TM DRX300, 300MHz for 1H). Peak positions are expressed in parts per million (ppm)downfield from tetramethylsilane. The peak multiplicities are denoted asfollows, s, singlet; d, doublet; t, triplet; q, quartet; quin, quintet;sex, sextet; sep, septet; non, nonet; dd, doublet of doublets; td,triplet of doublets; dt, doublet of triplets; m, multiplet.

The following abbreviations have the indicated meanings:

(Boc)₂O=di-tert-butyl dicarbonate

brine=saturated aqueous sodium chloride

CDCl₃=deuterated chloroform

CsCO₃=cesium carbonate

DCE=dichloroethane

DCM=dichloromethane

DEAD=diethyl azodicarboxylate

DHP=3,4-dihydro-2H-pyran

DMF=N,N-dimethylformamide

DMSO-d₆=deuterated dimethylsulfoxide

ESIMS=electron spray mass spectrometry

EtOAc=ethyl acetate

Et₃SiH=triethylsilane

HCl=hydrochloric acid

HOAc=acetic acid

KOAc=potassium acetate

KOH=potassium hydroxide

K₃PO₄=potassium phosphate

LAH=lithium aluminum hydride

MeOH=methanol

MgSO₄=magnesium sulfate

NaBH₄=sodium borohydride

NaBH(OAc)₃=sodium triacetoxy borohydride

NaCNBH₃=sodium cyanoborohydride

Na₂CO₃=sodium carbonate

NaHCO₃=sodium bicarbonate

NaHSO₃=sodium bisulfite

NaHSO₄=sodium bisulfate

NaOAc=sodium acetate

NMR=nuclear magnetic resonance

ON=overnight

PE=petroleum ether

Pd/C=palladium on carbon

Pd₂(dba)₃=tris(dibenzylideneacetone)dipalladium(0)

Pd(dppf)₂Cl₂=1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride

Pd(PPh₃)₂Cl₂=dichloro-bis(triphenylphosphine)palladium (II)

Pd(PPh₃)₄=tetrakis(triphenylphosphine)palladium(0)

PPh₃=triphenylphosphine

PPTS=pyridinium p-toluenesulfonate

rt=room temperature

SEM=2-(trimethylsilyl)ethoxymethyl

TEA=triethylamine

TFA=trifluoroacetic acid

THF=tetrahydrofuran

TLC=thin layer chromatography

The following example schemes are provided for the guidance of thereader, and collectively represent an example method for making thecompounds provided herein. Furthermore, other methods for preparingcompounds of the invention will be readily apparent to the person ofordinary skill in the art in light of the following reaction schemes andexamples. The skilled artisan is thoroughly equipped to prepare thesecompounds by those methods given the literature and this disclosure. Thecompound numberings used in the synthetic schemes depicted below aremeant for those specific schemes only, and should not be construed as orconfused with same numberings in other sections of the application.Unless otherwise indicated, all variables are as defined above.

General Procedures

Compounds of Formula I of the present invention can be prepared asdepicted in Scheme 1.

Scheme 1 describes a method for preparation of indazole derivatives(VIII) by first reacting5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde (II) withbis(pinacolato)diboron to form the borate ester (III). Suzuki couplingwith various bromides (IV) yields indazole derivatives (V). Aldehyde (V)is reacted with various 1,2-diamines (VI) to produce (VII). Finaldeprotection of the pyrazole nitrogen yields the desired indazolederivatives (VIII).

Alternatively, compounds of Formula I of the present invention can beprepared as depicted in Scheme 2.

Scheme 2 describes an alternative method for preparation of indazolederivatives (VIII) by first formylating 5-bromo-1H-indole (IX) toproduce 5-bromo-1H-indazole-3-carbaldehyde (X) followed by protectionwith either SEM-Cl or DHP to give the protected aldehyde (XI). Aldehyde(XI) is then reacted with bis(pinacolato)diboron to form the borateester (XII). Suzuki coupling with various bromides (IV) yields indazolederivatives (XIII). Aldehyde (XIII) is reacted with various 1,2-diamines(VI) to produce (XIV). Final deprotection of the pyrazole nitrogenyields the desired indazole derivatives (VIII).

Illustrative Compound Examples

Preparation of intermediate (II) is depicted below in Scheme 3.

Step 1

1H-indazole-3-carboxylic acid (XV) (100 g, 617 mmol) in DMF was treatedwith carbonyldiimidazole (110 g, 678 mmol) at room temperature until theevolution of gas ceased (ca. 15 minutes). The reaction was heated to60-65° C. for two hours and then allowed to cool to room temperature.N,O-Dimethylhydroxylamine-HCl (66.2 g, 678 mmol) was added as a solidand the mixture was heated to 65° C. for 3 hours. The reaction wasconcentrated to a paste and taken up in DCM, and washed subsequentlywith water and 2N HCl. The product could be seen coming out of solution.The solid was filtered and rinsed separately with EtOAc. The EtOAc andDCM layers were separately washed with sodium bicarbonate followed bybrine, dried over MgSO₄ and concentrated under reduced pressure. Theresulting solids were combined, triturated with 1:1 mixture ofDCM-ether, filtered, and dried to produceN-methoxy-N-methyl-1H-indazole-3-carboxamide (XVI) as a white solid (100g, 487 mmol, 79% yield). ¹H NMR (DMSO-d₆) δ ppm 3.46 (s, 3H), 3.69-3.85(m, 3H), 7.13-7.31 (m, 1H), 7.41 (t, J=7.25 Hz, 1H), 7.56-7.65 (m, 1H),7.93-8.08 (m, 1H); ESIMS found for C₁₀H₁₁N₃O₂ m/z 206 (M+H).

Step 2

To the N-methoxy-N-methyl-1H-indazole-3-carboxamide (XVI) (20 g, 97.4mmol) in DCM (1 L) was added bis(trifluoroacetoxy)iodobenzene (46 g, 107mmol) followed by portionwise addition of iodine (14.84 g, 58.5 mmol) atroom temperature. After 1 hour, 600 mL of saturated NaHSO₃ was added anda solid began to precipitate which was filtered and rinsed with excessDCM. The filtrate was washed with brine, dried over MgSO₄, concentratedand the remaining solid was triturated with a minimal amount of DCM. Thecombined solids were dried under vacuum over KOH to produce5-iodo-N-methoxy-N-methyl-1H-indazole-3-carboxamide (XVII) as a whitesolid (23.2 g, 70 mmol, 72% yield). ¹H NMR (DMSO-d₆) δ ppm 3.45 (s, 4H),3.77 (s, 4H), 7.45-7.54 (m, 1H), 7.66 (dd, J=8.81, 1.51 Hz, 1H), 8.40(d, J=1.01 Hz, 1H); ESIMS found for C₁₀H₁₀IN₃O₂ m/z 331 (M+H).

Step 3

A mixture of 5-iodo-N-methoxy-N-methyl-1H-indazole-3-carboxamide (XVII)(16.5 g, 50 mmol), 3,4-dihydro-2H-pyran (10.3 mL, 113 mmol) and PPTS(0.12 g, 0.6 mmol) in DCM was heated to reflux for κ hours. The solutionwas poured into a saturated NaHCO₃ solution, the layers were separated,and the aqueous layer was extracted with DCM. The combined organiclayers were washed with 5% aqueous citric acid and brine, dried overMgSO₄, and concentrated. The crude product was purified on a silica gelcolumn (100% EtOAc→3:97 MeOH:DCM) to provide5-iodo-N-methoxy-N-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxamide(XVIII) as a white viscous oil (19.1 g, 46 mmol, 92% yield). ¹H NMR(DMSO-d₆) δ ppm 1.28-1.84 (m, 6H), 3.43 (s, 3H), 3.60-4.04 (s, 5H),5.86-6.08 (m, 1H), 7.45-7.87 (m, 2H), 8.39 (s, 1H); ESIMS found forC₁₅H₁₈IN₃O₃ m/z 416 (M+H).

Step 4

Lithium aluminum hydride (160 mg, 4.21 mmol) was added in portions to acooled (0° C.) solution of5-iodo-N-methoxy-N-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxamide(XVIII) (1.46 g, 3.5 mmol) in THF. Stirring was continued at 0° C. untilthe reaction was completed, approximately 30 min. The reaction wasquenched by the slow addition of EtOAc at 0° C., and the whole mixturewas poured into 0.4 N NaHSO₄. The organic layer was washed with brine,dried over MgSO₄, concentrated, and purified on a silica gel column(100% EtOAc→3:97 MeOH:DCM) to give5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde (II) as awhite solid (0.90 g, 3.15 mmol, 72% yield). ¹H NMR (DMSO-d₆) δ ppm1.50-1.71 (m, 2H), 1.71-1.87 (m, 1H), 1.97-2.15 (m, 2H), 2.31-2.42 (m,1H), 3.66-3.99 (m, 2H), 5.96-6.17 (m, 1H), 7.78 (d, J=6 Hz, 1H), 7.84(d, J=6 Hz, 1H), 8.50 (s, 1H), 10.13 (s, 1H); ESIMS found forC₁₃H₁₃IN₂O₂ m/z 357 (M+H).

Preparation of SEM protected intermediate (XX) is depicted below inScheme 4.

Step 1

A solution of NaNO₂ (110.4 g, 1.6 mol, 8 eq) in water (200 mL) was addeddropwise to a solution of 5-bromoindole (IX) (39.2 g, 0.2 mol, 1 eq) inacetone (1000 mL) stirred at −10→0° C., while adding NaNO₂ the solutiontemperature was maintained below 20° C. An aqueous 2N HCl solution (480mL) was added slowly to the solution with vigorously stirring whilekeeping the internal temperature between 0 and 20° C. The solution wasfurther stirred at 20° C. for 3 h after the addition. The solution wasconcentrated under reduced pressure to remove acetone while keeping thetemperature below 35° C. The solid was collected by filtration andtransferred to a flask. Cold (−10° C.) DCM (200 mL) was added andstirred for 30 min at −5° C., the solids were filtered and dried undervacuum at 40° C. to get 5-bromo-1H-indazole-3-carbaldehyde (X) (34.0 g,151 mmol, 76% yield) as a brown solid. ESIMS found for C₈H₅BrN₂O m/z 225(M+H).

Step 2

To a suspension of NaH (6.6 g, 166 mmol, 1.10 eq) in DMF (500 mL) wasadded a solution of 5-bromo-1H-indazole-3-carbaldehyde (X) (34.0 g, 151mmol, 1.00 eq) in DMF (50 mL) dropwise at 0° C. over a period of 30 min.The mixture was stirred at room temperature for 2 h, then SEM-Cl (26.4g, 159 mmol, 1.08 eq) was added dropwise and the mixture was stirred atroom temperature for another 3 h. Then the mixture was poured into anice-water mixture (1000 mL) and extracted with EtOAc (300 mL×3), theorganic phases were combined, dried over Na₂SO₄, filtered andconcentrated in vacuo, the resultant residue was purified by flashchromatography on silica gel (PE:EtOAc=20:1→10:1) to afford5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-3-carbaldehyde(XIX) as a mixture of regioisomers (53.0 g, 151 mmol, 100% yield) as ayellow oil. ESIMS found for C₁₄H₁₉BrN₂O₂Si m/z 355 (M+H).

Step 3

To a solution of the mixed 5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-3-carbaldehyde (XIX) (53.0 g, 151 mmol, 1.0 eq),bis(pinacolato)diboron (38.0 g, 150 mmol, 1.0 eq) and KOAc (44.0 g, 450mmol, 3.00 eq) in DMF (1000 mL) was added Pd(dppf)Cl₂ (7.7 g, 10.5 mmol,0.07 eq). The mixture was stirred at 90° C. under nitrogen for 10 h. Themixture was filtered; the filtrate was poured onto water (1000 mL) andextracted with EtOAc (500 mL×3). The combined organic phases were dried,filtered and concentrated in vacuo. The resultant residue was purifiedby flash chromatography on silica gel (PE:EtOAc=10:1→1:1) to give the5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-3-carbaldehyde(XX) as a mixture of regioisomers (42.9 g, 106 mmol, 71% yield) as ayellow oil. ESIMS found for C₂₀H₃₁BN₂O₄Si m/z 403 (M+H).

Preparation of THP protected intermediate (XXI) is depicted below inScheme 5.

Step 1

Procedure can be found in Scheme 4, Step 1.

Step 2

Procedure can be found in Scheme 3, Step 3.5-Bromo-1-(tetrahydro-2H-pyran-2-yl)-3a,7a-dihydro-1H-indazole-3-carbaldehydeXXI was isolated as a white solid (16.4 g, 52.7 mmol, 39.6% yield). ¹HNMR (DMSO-d₆, 500 MHz) δ ppm 1.57-1.65 (m, 2H), 1.72-1.83 (m, 1H),2.02-2.11 (m, 2H), 2.33-2.44 (m 1H), 3.76-3.83 (m, 1H), 3.84-3.93 (m,1H), 6.08 (dd, J=2.5 Hz, 9 Hz, 1H), 7.72 (dd, J=1.5 Hz, J=8.5 Hz, 1H),7.92 (d, J=9 Hz, 1H), 8.28 (d, J=2 Hz, 1H), 10.17 (s, 1H); ESIMS foundC₁₃H₁₅BrN₂O₂ m/z 311.0 (M+H).

Preparation of intermediate N-(5-bromopyridin-3-yl)isobutyramide (XXIV)is depicted below in Scheme 6.

Step 1

3-Amino-5-bromo pyridine (XXII) (1 eq) was dissolved in DCM and cooledto 0° C. before adding pyridine (2.2 eq) and isobutyryl chloride (XXIII)(1.1 eq). The reaction mixture was stirred at room temperature for 15 huntil TLC showed the reaction was complete. The reaction mixture wasdiluted with DCM and washed with water. The organic extract was dried,concentrated and purified by column chromatography using silica gel(100-200 mesh) to afford N-(5-bromopyridin-3-yl)isobutyramide (XXIV) asan off-white solid, (71% yield). ¹H NMR (CDCl₃) δ ppm 8.55-8.35 (m, 3H),7.32 (s, 1H), 2.59-2.48 (m, 1H), 1.28-1.27 (d, 6H); ESIMS foundC₉H₁₁BrN₂O m/z 243.05 (M+H).

The following compounds were prepared in accordance with the proceduredescribed in the above Scheme 6.

N-(5-Bromopyridin-3-yl)propionamide (XXV): Off white solid (92% yield).¹H NMR (DMSO-d₆) δ ppm 1.09 (t, J=7.54 Hz, 3H), 2.36 (q, J=7.54 Hz, 2H),8.36 (m, 2H), 8.65 (d, J=2.07 Hz, 1H), 10.26 (s, 1H); ESIMS foundC₈H₉BrN₂O m/z 231 (M+H).

N-(5-Bromopyridin-3-yl)butyramide (XXVI): Yellow solid (2.1 g, 8.64mmol, 88.8% yield). ESIMS found C₉H₁₁BrN₂O m/z 243 (M+H).

N-(5-Bromopyridin-3-yl)pentanamide (XXVII): Yellow solid (2.0 g, 7.78mmol, 85.3% yield). ESIMS found C₁₀H₁₃BrN₂O m/z 257 (M+H).

N-(5-Bromopyridin-3-yl)-3-methylbutanamide (XXVIII): Off white solid,(67% yield), ¹H NMR (CDCl₃, 500 MHz) δ ppm 8.55-8.42 (m, 3H), 7.62 (s,1H), 2.31-2.18 (m, 3H), 1.02-1.01 (d, J=6 Hz, 6H); ESIMS foundC₁₀H₁₃BrN₂O m/z 258.80 (M+H).

N-(5-Bromopyridin-3-yl)-3,3-dimethylbutanamide (XXIX): Yellow solid (1.7g, 6.27 mmol, 78.6% yield). ESIMS found C₁₁H₁₅BrN₂O m/z 271 (M+H).

N-(5-Bromopyridin-3-yl)pivalamide (XXX): Off-white solid (1.082 g, 4.22mmol, 73.1% yield). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm 1.23 (s, 9H), 8.37(d, J=2 Hz, 1H), 8.39 (t, J=2 Hz, 1H), 8.80 (d, J=2 Hz, 1H), 9.58 (brs,1H); ESIMS found C₁₀H₁₃BrN₂O m/z 257.0 (M+H).

N-(5-Bromopyridin-3-yl)-2-phenylacetamide (XXXI): White solid (2.5 g,8.59 mmol, 77.9% yield). ESIMS found C₁₃H₁₁BrN₂O m/z 291 (M+H).

N-(5-Bromopyridin-3-yl)benzamide (XXXII): White solid (2.7 g, 9.74 mmol,60% yield). ESIMS found C₁₂H₉BrN₂O m/z 277 (M+H).

N-(5-Bromopyridin-3-yl)cyclopropanecarboxamide (XXXIII): Off-whitesolid, (83% yield), ¹H NMR (CDCl₃, 500 MHz) δ ppm 8.46-8.39 (m, 3H),7.54 (bs, 1H), 1.56-1.50 (m, 1H), 1.13-1.07 (m, 2H), 0.96-0.90 (m, 2H);ESIMS found for C₉H₉BrN₂O m/z 240.9 (M+H).

N-(5-Bromopyridin-3-yl)cyclobutanecarboxamide (XXXIV): Yellow solid (2.1g, 6.27 mmol, 86.6% yield). ESIMS found C₁₀H₁₁BrN₂O m/z 255 (M+H).

N-(5-Bromopyridin-3-yl)cyclopentanecarboxamide (XXXV): Yellow solid (1.9g, 7.06 mmol, 80.2% yield). ESIMS found C₁₁H₁₃BrN₂O m/z 269 (M+H).

N-(5-bromopyridin-3-yl)cyclohexanecarboxamide (XXXVI): Yellow solid (2.0g, 7.06 mmol, 84.3% yield). ESIMS found C₁₂H₁₅BrN₂O m/z 283 (M+H).

N-(5-bromopyridin-3-yl)-1-methylpiperidine-4-carboxamide (XXXVII): Waxybrown solid, (43%, yield), ¹H NMR (CDCl₃, 500 MHz) δ ppm 1.67 (dq, 2H),1.77 (d, 2H), 1.96 (t, 2H), 2.20 (s, 3H), 2.31 (m, 1H), 2.86 (d, 2H),8.36 (s, 1H), 8.40 (s, 1H), 8.67 (s, 1H) m 10.34 (s, 1H); ESIMS foundC₁₂H₁₆BrN₃O m/z 297.8 (M^(Br79)+H) and 299.8 (M^(Br81)+H).

N-(5-bromopyridin-3-yl)methanesulfonamide (XXXVIII): Off-white solid,(67%, yield), ¹H NMR (CDCl₃, 500 MHz) δ ppm 3.14 (s, 3H), 7.80 (s, 1H),8.40 (s, 1H), 8.41 (s, 1H), 10.28 (brs, 1H); ESIMS found C₆H₇BrN₂O₂S m/z250.9 (M^(Br79)+H) and 252.9 (M^(Br81)+H).

N-(5-bromopyridin-3-yl)benzenesulfonamide (XXXIX): White solid, (84%,yield), ¹H NMR (DMSO-d₆, 500 MHz) δ ppm 7.58-7.61 (m, 2H), 7.65-7.67 (m,2H), 7.83 (d, 2H), 8.15 (d, 1H), 8.38 (d, 1H), 10.87 (brs, 1H); ESIMSfound C₁₁H₉BrN₂O₂S m/z 314.3 (M^(Br81)+H).

Preparation of intermediate (XLI) is depicted below in Scheme 7.

Step 1

To a solution of 3,5-dibromopyridine (XL) (1.68 g, 7.1 mmol) in dioxane(14 mL) was added morpholine (682 mg, 7.8 mmol), CsCO₃ (3.24 g, 9.93mmol) and xantphos (123 mg, 0.21 mmol). The solution was degassed beforeadding Pd₂(dba)₃ (195 mg, 0.21 mmol). The reaction was microwaved at 90°C. for 4 h. The reaction was poured into a mixture of CHCl₃/H₂O; theaqueous layer was separated, washed with water, then brine andconcentrated under vacuum. The crude product was purified on a silicagel column (100% hexane→1:3 EtOAc:hexane) to give4-(5-bromopyridin-3-yl)morpholine (XLI) as a yellow solid (1.12 g, 4.6mmol, 65% yield). ESIMS found C₉H₁₁BrN₂O m/z 244 (M+H).

The following compound was prepared in accordance with the proceduredescribed in the above Scheme 7.

1-(5-bromopyridin-3-yl)-4-methylpiperazine (XLII): Brown oil (50%,yield), ¹H NMR (DMSO-d₆, 500 MHz) δ ppm 2.21 (s, 3H), 2.41-2.43 (m, 4H),3.22-3.24 (m, 4H), 7.51-7.52 (m, 1H), 8.02 (d, J=1.9 Hz, 1H), 8.28 (d,J=2.6 Hz, 1H); ESIMS found C₁₀H₁₄BrN₃ m/z 256 (M+H).

Preparation of intermediate 5-bromo-N,N-dimethylpyridin-3-amine (XLIII)is depicted below in Scheme 8.

Step 1

To a solution of 3,5-dibromopyridine (XL) (2.37 g, 10.0 mmol) in dry DMF(20.0 mL) was added K₂CO₃ (4.5 g, 33 mmol) and dimethylaminohydrochloride (1.79 g, 22 mmol). The mixture was heated overnight at200° C. in a sealed tube. The solution was cooled to room temperatureand excess DMF was removed under vacuum. The residue was partitionedbetween EtOAc and water. The organic phase was separated. The aqueousphase was washed with EtOAc and the combined organic phases were driedover MgSO₄, and concentrated to afford5-bromo-N,N-dimethylpyridin-3-amine (XLIII) as an off-white solid (1.78g, 8.85 mmol, 88% yield). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm 2.94 (s, 6H),7.25 (t, J=2 Hz, 1H), 7.91 (d, J=2 Hz, 1H), 8.07 (d, J=2 Hz, 1H); ESIMSfound C₇H₉BrN₂ m/z 201.1 (M+H).

Preparation of intermediate 5-bromo-N-isopropylpyridin-3-amine (XLIV) isdepicted below in Scheme 9.

Steps 1

To a solution of 5-bromopyridin-3-amine (XXII) (535 mg, 3.09 mmol) inMeOH (62 mL) was added acetone (296 μL, 4.02 mL). The pH was adjusted to4 using HOAc and stirred for 30 min. NaCNBH₃ (272 mg, 4.33 mmol) wasadded and stirred at room temperature overnight. The MeOH was removedunder vacuum and the residue was partitioned between EtOAc and saturatedaqueous NaHCO₃. The organic layer was dried over MgSO₄ and evaporatedunder vacuum. The crude product was purified on a silica gel column(100% hexane→90:10 hexane:EtOAc) to produce5-bromo-N-isopropylpyridin-3-amine (XLIV) as an oil which slowlysolidified into an off-white solid (309 mg, 1.44 mmol, 47% yield). ¹HNMR (DMSO-d₆, 500 MHz) δ ppm 1.12 (d, J=6.3 Hz, 6H), 3.55-3.59 (m, 1H),6.03 (d, J=7.9 Hz, 1H), 7.05-7.06 (m, 1H), 7.75 (d, J=2 Hz, 1H), 7.90(d, J=2 Hz, 1H); ESIMS found C₈H₁₁BrN₂ m/z 215 (M+H).

Preparation of intermediate 1-(5-bromopyridin-3-yl)-N,N-dimethylmethanamine (XLVI) is depicted below in Scheme 10.

Step 1

To a solution of 5-bromonicotinaldehyde (XLV) (5.0 g, 26.9 mmol) in DCE(108 mL) was added dimethylamine-HCl (4.39 g, 53.8 mmol) and TEA (7.5 g,53.8 mmol). The reaction was stirred at room temperature for 1 h.NaBH(OAc)₃ was added and the reaction was stirred overnight at roomtemperature. The reaction was diluted with DCM and sat. aq. NaHCO₃. Theorganic layer was separated, washed with water, brine, dried andconcentrated under vacuum to produce1-(5-bromopyridin-3-yl)-N,N-dimethylmethanamine (XLVI) as a brown liquid(5.36 g, 24.9 mmol, 92.6% yield). ¹H NMR (CDCl₃) δ ppm 2.15 (s, 6H),3.43 (s, 2H), 7.94 (s, 1H), 8.47 (d, J=1.1 Hz, 1H), 8.59 (d, J=2.2 Hz,1H); ESIMS found C₈H₁₁BrN₂ m/z 215 (M^(Br79)+H) and 217 (M^(Br81)+H).

The following intermediates were prepared in accordance with theprocedure described in the above Scheme 10.

3-Bromo-5-(pyrrolidin-1-ylmethyl)pyridine (XLVII): Golden liquid (1.35g, 97% yield). ¹H NMR (DMSO-d₆) 1.68-1.71 (m, 4H), 2.42-2.44 (m, 4H),3.60 (s, 2H), 7.96 (s, 1H), 8.48 (d, J=2 Hz, 1H), 8.58 (d, J=3 Hz, 1H);ESIMS found for C₁₀H₁₃BrN₂ m/z 242 (M+H).

3-Bromo-5-((3,3-difluoropyrrolidin-1-yl)methyl)pyridine (XLVIII): Brownoil (6.4 g, 81% yield). ESIMS found for C₁₀H₁₁BrF₂N₂ m/z 277.0 (M+H).

3-Bromo-5-(piperidin-1-ylmethyl)pyridine (XLIX): Brown liquid (13.1 g,94% yield). ¹H NMR (DMSO-d₆) 1.36-1.39 (m, 2H), 1.46-1.51 (m, 4H),2.31-2.32 (m, 4H), 3.46 (s, 2H), 7.94 (s, 1H), 8.47 (d, J=2 Hz, 1H),8.58 (d, J=3 Hz, 1H); ESIMS found for C₁₁H₁₅BrN₂ m/z 257 (M+H).

N-((5-Bromopyridin-3-yl)methyl)ethanamine (L): Golden liquid (1.29 g,6.00 mmol, 60% yield). ESIMS found for C₈H₁₁BrN₂ m/z 215 (M+H).

N-Benzyl-1-(5-bromopyridin-3-yl)methanamine (LI): Golden liquid (77 mg,0.28 mmol, 25% yield). ESIMS found for C₁₃H₁₃BrN₂ m/z 277 (M+H).

Preparation of intermediate tert-butyl (5-bromopyridin-3-yl)methyl(cyclopentylmethyl)carbamate (LVI) is depicted below in Scheme 11.

Step 1

To a solution of 5-bromonicotinaldehyde (XLV) (2.0 g, 10.8 mmol, 1 eq)in MeOH (20 mL) was added NaBH₄ (2.4 g, 64.9 mmol, 6 eq) and thereaction mixture was stirred at room temperature for 3 h. The mixturewas concentrated in vacuo and the residue was diluted in water (15 mL),the aqueous phase was extracted with DCM (10 mL×3). The combined organiclayers were dried over MgSO₄, filtered and concentrated in vacuo toafford (5-bromopyridin-3-yl)methanol (LII) (1.8 g, 9.57 mmol, 90.0%yield) as a colorless oil. ¹H NMR (CDCl₃, 500 MHz) δ ppm 4.73 (s, 2H),7.90 (s, 1H), 8.47 (s, 1H), 8.57 (s, 1H). ESIMS found for C₆H₆BrNO m/z188 (M+H).

Step 2

To a stirred solution of (5-bromopyridin-3-yl)methanol (LII) (1.60 g,8.5 mmol, 1 eq), phthalimide (1.24 g, 8.5 mmol, 1 eq) and PPh₃ (3.33 g,12.75 mmol, 1.5 eq) in anhydrous THF (15 mL) was added DEAD (2.21 g,12.75 mmol, 1.5 eq) dropwise at 0° C. under N2. Then the reactionmixture was stirred at room temperature for 6 h. The mixture was washedwith saturated NaHCO₃ solution (15 mL), water (15 mL) and brine (15 mL)subsequently. The organic layers were dried over MgSO₄, concentratedunder reduced pressure, the resultant residue was purified by flashchromatography on silica gel (PE:EtOAc=4:1) to give2-((5-bromopyridin-3-yl)methyl)isoindoline-1,3-dione (LIII) (2.5 g, 7.88mmol, 82.3% yield) as a white solid. ESIMS found for C₁₄H₉BrN₂O₂ m/z 317(M+H).

Step 3

A solution of 2-((5-bromopyridin-3-yl)methyl)isoindoline-1,3-dione(LIII) (1.9 g, 6.0 mmol, 1 eq) and hydrazine hydrate (2.0 g, 40 mmol, 6eq) in EtOH (20 mL) was heated at 70° C. for 3 h. The mixture wasfiltered through a Celite® pad and the filtrate was concentrated invacuo, the crude product was dissolved in 1N HCl solution (15 mL) andconcentrated to dryness, then it was washed with acetone (10 mL×3), theprecipitate was collected by filtration, dried in vacuo to give(5-bromopyridin-3-yl)methanamine (LIV) (1.3 g, 6.95 mmol, 97.7% yield)as a white solid. ¹H NMR (D₂O, 500 MHz) δ ppm 4.34 (s, 2H), 8.56 (s,1H), 8.75 (d, J=1.2 Hz, 1H), 8.91 (d, J=1.6 Hz, 1H). ESIMS found forC₆H₇BrN₂ m/z 187 (M+H).

Step 4

A solution of (5-bromopyridin-3-yl)methanamine (LIV) (1.30 g, 5.8 mmol,1.0 eq), cyclopentanecarbaldehyde (0.57 g, 5.8 mmol, 1.0 eq) and TEA(0.60 g, 5.8 mmol, 1.0 eq) in MeOH (15 mL) was stirred at roomtemperature for 2 h. Then NaBH₃CN (1.98 g, 34.6 mmol, 6.0 eq) was addedand the mixture was stirred at the same temperature for another 3 h. Thesolvent was removed under reduced pressure and the residue was dilutedin water (20 mL) and extracted with DCM (10 mL×3), combined organiclayers were dried over MgSO₄ and concentrated in vacuo to give1-(5-bromopyridin-3-yl)-N-(cyclopentylmethyl)methanamine (LV) (1.23 g,4.57 mmol, 79.3% yield) as a brown oil. ESIMS found for C₁₂H₁₇BrN₂ m/z269 (M+H).

Step 5

To a solution of 1-(5-bromopyridin-3-yl)-N-(cyclopentylmethyl)methanamine (LV) (1.00 g, 3.7 mmol, 1 eq) and TEA (0.93 g, 9.2 mmol, 2.5eq) in DCM (20 mL) was added portionwise (Boc)₂O (0.85 g, 4.0 mmol, 1.1eq) at 0° C., the reaction mixture was stirred at room temperature for 1h. The mixture was washed with water (10 mL), brine (10 mL), the organiclayer was separated, dried over MgSO₄ and concentrated in vacuo to givetert-butyl (5-bromopyridin-3-yl)methyl (cyclopentylmethyl)carbamate(LVI) (1.25 g, 3.38 mmol, 91.9% yield) as a white solid. ESIMS found forC₁₇H₂₅BrN₂O₂ m/z 369 (M+H).

Preparation of intermediate (LX) is depicted below in Scheme 12.

Step 1

A mixture of 3-nitropyridin-4-amine (LVII) (10 g, 71.94 mmol) and aceticacid (120 mL) was added to a sealed tube followed by addition of NaOAc(29.50 g, 93.52 mmol) and dropwise addition of bromine (4.7 ml 359.7mmol) under stirring. The sealed tube was heated at 100° C. for 28 huntil TLC showed consumption of starting material. The reaction mixturewas concentrated to obtain a solid which was dissolved in water,basified with NaHCO₃ and extracted with EtOAc. The combined organicextracts were dried and concentrated to produce3-bromo-5-nitropyridin-4-amine (LVIII) as a yellow solid (12 g, 55 mmol,77% yield). ¹H NMR (DMSO-d₆) δ ppm 9.19 (s, 1H), 8.58 (s, 1H); ESIMSfound for C₅H₄BrN₃O₂ m/z 217, 219 (M+, M+2).

Step 2

A solution of 3-bromo-5-nitropyridin-4-amine (LVIII) (6 g, 26 mmol),pyridin-3-ylboronic acid (3.54 g, 29 mmol), 1 N Na₂CO₃ solution (78 ml)and 1,4-dioxane (150 mL) was degassed with argon thrice. Pd(PPh₃)₂Cl₂(927 mg, 5 mmol %) was added to the reaction and the solution wasrefluxed for 15 h until TLC showed the reaction was complete. Thereaction was passed through a pad of Celite® and then concentrated underreduced pressure. The reaction mixture was concentrated and the residuewas taken up in EtOAc. The organic extract was washed with water, driedand concentrated under vacuum. The crude product was purified on asilica gel column (100% EtOAc→2:98 MeOH:DCM) to give5-nitro-3,3′-bipyridin-4-amine (LIX) as a yellow solid (5 g, 23.1 mmol,87% yield). ¹H NMR (CDCl₃, 500 MHz) δ ppm 9.31 (s, 1H), 8.80-8.79 (m,1H), 8.70 (s, 1H), 8.23 (s, 1H), 7.80-7.73 (m, 1H), 7.52-7.48 (m, 1H).ESIMS found C₁₀H₈N₄O₂ m/z 216.95 (M+H).

Step 3

To a solution of 5-nitro-3,3′-bipyridin-4-amine (LIX) (5 g, 23 mmol) inMeOH (20 mL) was added 10% Pd/C. The solution was purged with hydrogenand stirred at room temperature under hydrogen for 15 h. The suspensionwas filtered through Celite® and the concentrated under vacuum toproduce 3,3′-bipyridine-4,5-diamine (LX) as off white solid (3.3 g, 17.7mmol, 76% yield). ¹H NMR (DMSO-d₆, 500 MHz): δ ppm 8.63-8.53 (m, 1H),7.90-7.83 (m, 1H), 7.75 (s, 1H), 7.58 (s, 1H), 7.48-7.43 (m, 2H), 6.13(bs, 2H), 5.31 (bs, 2H). ESIMS found C₁₀H₁₀N₄ m/z 187.10 (M+H).

The following compounds were prepared in accordance with the proceduredescribed in the above Scheme 12.

3,4′-Bipyridine-4,5-diamine (LXI): Light tan solid, (84% yield). ESIMSfound C₁₀H₁₀N₄ m/z 187.0 (M+H).

2,3′-Bipyridine-4′,5′-diamine (LXII): Tan amorphous solid, (76% yield).ESIMS found C₁₀H₁₀N₄ m/z 187.0 (M+H).

5-(3-Fluorophenyl)pyridine-3,4-diamine (LXIII): Off white solid, (76%yield), ¹H NMR (CDCl₃, 500 MHz) δ ppm 4.72 (s, 2H), 5.07 (s, 2H),7.17-7.23 (m, 3H), 7.44 (s, 1H), 7.48-7.52 (m, 1H), 7.68 (s, 1H); ESIMSfound C₁₁H₁₀FN₃ m/z 204.1 (M+H).

5-(4-Fluorophenyl)pyridine-3,4-diamine (LXIV): Light yellow solid, (97%yield). ESIMS found C₁₁H₁₀FN₃ m/z 204.3 (M+H).

5-(2-Fluorophenyl)pyridine-3,4-diamine (LXV): Light red solid, (44%yield). ESIMS found C₁₁H₁₀FN₃ m/z 204.4 (M+H).

5′-Fluoro-3,3′-bipyridine-4,5-diamine (LXVI): Off white solid, (100%yield), ¹H NMR (CDCl₃, 500 MHz) δ ppm 4.78 (s, 2H), 5.28 (s, 2H), 7.46(s, 1H), 7.70 (s, 1H), 7.73-7.76 (m, 1H), 8.44-8.45 (m, 1H), 8.56 (d,J=2.8 Hz, 1H); ESIMS found C₁₀H₉FN₄ m/z 205 (M+H).

5-(Furan-3-yl)pyridine-3,4-diamine (LXVII): Light pink solid, (68%yield). ESIMS found C₉H₉N₃O m/z 176.0 (M+H).

5-(Thiophen-3-yl)pyridine-3,4-diamine (LXVIII): Light brown amorphoussolid, (100% yield). ESIMS found C₉H₉N₃S m/z 192.0 (M+H).

5-(thiophen-2-yl)pyridine-3,4-diamine (LXIX): White amorphous solid,(1.257 g, 6.57 mmol, 100% yield). ESIMS found C₉H₉N₃S m/z 192.2 (M+H).

Preparation of intermediate (LXXI) is depicted below in Scheme 13.

Step 1

A solution of 3-bromo-5-nitropyridin-4-amine (LVIII) (618 mg, 2.83 mmol)in 1-methylpiperazine (1 mL, 8.51 mmol) was heated at 140° C. overnight.The reaction was poured into an EtOAc/H₂O mixture; the organic layer wasseparated, dried over MgSO₄ and concentrated under vacuum. The crudeproduct was purified on a silica gel column (100% CHCl₃→3:97 MeOH(7NNH₃):CHCl₃) to give 3-(4-methylpiperazin-1-yl)-5-nitropyridin-4-amine(LXX) as a yellow solid (382 mg, 1.61 mmol, 56.7% yield). ¹H NMR (CDCl₃,500 MHz) δ ppm 2.20 (s, 3H), 2.35-2.37 (m, 4H), 4.52-3.54 (m, 4H), 5.96(s, 1H), 7.42 (s, 2H), 8.78 (s, 1H); ESIMS found C₁₀H₁₅N₅O₂ m/z 238(M+H).

Step 2

To a solution of 3-(4-methylpiperazin-1-yl)-5-nitropyridin-4-amine (LXX)(382 mg, 1.61 mmol) in MeOH (11 mL) was added 10% Pd/C. The solution waspurged with hydrogen and stirred at room temperature under hydrogen for4 h. The suspension was filtered through Celite® and the concentratedunder vacuum to produce 5-(4-methylpiperazin-1-yl)pyridine-3,4-diamine(LXXI) as purple solid (330 mg, 1.59 mmol, 99% yield). ¹H NMR (DMSO-d₆,500 MHz): δ 2.18 (s, 3H), 2.34-2.36 (m, 4H), 3.13-3.16 (m, 4H), 3.89 (s,2H), 5.20 (s, 2H), 5.94 (s, 1H), 7.31 (s, 1H); ESIMS found C₁₀H₁₇N₅ m/z208 (M+H).

The following compounds were prepared in accordance with the proceduredescribed in the above Scheme 13.

5-Morpholinopyridine-3,4-diamine (LXXII): ¹H NMR (DMSO-d₆, 500 MHz) δppm 3.10 (t, 4H), 3.65 (t, 4H), 3.93 (brs, 2H), 5.23 (brs, 2H), 5.94 (s,1H), 7.33 (s, 1H); ESIMS found C₉H₁₄N₄O m/z 195 (M+H).

5-(Piperidin-1-yl)pyridine-3,4-diamine (LXXIII): Purple solid, (83%yield). ESIMS found C₁₀H₁₆N₄ m/z 193.1 (M+H).

Preparation of intermediate (LXXVIII) is depicted below in Scheme 14.

Step 1

To a solution of 1,3-dibromo-5-fluorobenzene (LXXIV) (4 g, 15.75 mmol)in toluene (50 mL) was added ^(t)BuOK (5.3 g, 47.25 mmol) andN¹,N¹,N²-trimethylethane-1,2-diamine (2.778 mL, 31.5 mmol). The reactionwas stirred at 110° C. overnight. The solvent was removed under vacuumand the residue was partitioned between EtOAc and water. The organiclayer was separated, washed with water, brine, dried over MgSO₄ andevaporated under vacuum. The crude product was purified on a silica gelcolumn (100% CHCl₃→5:95 MeOH:CHCl₃) to produceN¹-(3-bromo-5-fluorophenyl)-N²,N²-dimethylethane-1,2-diamine (LXXV) as abrown viscous oil (1.02 g, 3.91 mmol, 24.8% yield). ¹H NMR (DMSO-d₆, 500MHz) δ ppm 2.17 (s, 6H), 2.40 (t, J=3.5 Hz, 2H), 3.01-3.09 (m, 2H), 6.10(t, J=5 Hz, 1H), 6.38 (dt, J=12 Hz, J=2 Hz, 1H), 6.51 (dt, J=8.5 Hz, J=2Hz, 1H), 6.60 (s, 1H); ESIMS found C₁₂H₁₆BrFN₂ m/z 261 (M+H).

Step 2-3

A solution ofN¹-(3-bromo-5-fluorophenyl)-N²,N²-dimethylethane-1,2-diamine (LXXV) (5g, 19.15 mmol), bis(pinacolato)diboron (5.83 g, 22.98 mmol), KOAc (5.63g, 57.45 mmol) and dry DMF (20 mL) was purged with argon. PdCl₂(dppf)₂(938 mg, 1.15 mmol) was added to the reaction and purged again withargon. The solution was heated at 95° C. for 2 h. Once TLC showed thedisappearance of (LXXV), the solution was cooled to room temperature. Tothis solution was added K₃PO₄ (6.09 g, 28.72 mmol),3-bromo-5-nitropyridin-4-amine (LVIII) (4.17 g, 19.15 mmol), Pd(PPh₃)₄(663 mg, 0.57 mmol) and water (4 mL). The solution was purged with argonand heated at 100° C. for 4 h. The solution was cooled to roomtemperature and then concentrated under reduced pressure. The residuewas partitioned between DCM and water. The aqueous phase was filteredthrough Celite® and concentrated under vacuum. The residue was purifiedon a silica gel column (100% CHCl₃→5:95 MeOH:CHCl₃) to giveN¹-(3-(4-amino-5-nitropyridin-3-yl)-5-fluorophenyl)-N²,N²-dimethylethane-1,2-diamine (LXXVII) as a yellow amorphous solid (3.30 g, 10.33mmol, 54.0% yield for 2 steps). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm 2.18 (s,6H), 2.44 (t, J=6.5 Hz, 2H), 3.12 (q, J=6 Hz, 2H), 6.01 (t, J=5 Hz, 1H),6.35 (d, J=9 Hz, 1H), 6.43 (s, 1H), 6.48 (dt, J=10 Hz, J=2 Hz, 1H), 7.32(brs, 2H), 8.10 (s, 1H), 9.01 (s, 1H); ESIMS found for C₁₅H₁₈FN₅O₂ m/z320.3 (M+H).

Step 4

To a solution ofN¹-(3-(4-amino-5-nitropyridin-3-yl)-5-fluorophenyl)-N²,N²-dimethylethane-1,2-diamine(LXXVII) (2.1 g, 6.58 mmol) in MeOH (40 mL) was added 10% Pd/C (300 mg,15% by wt). The solution was purged with hydrogen and stirred for 4 h atroom temperature under hydrogen. The suspension was filtered throughCelite® and concentrated under vacuum to produce5-(3-(2-(dimethylamino)ethylamino)-5-fluorophenyl)pyridine-3,4-diamine(LXXVIII) as a brown solid (1.90 g, 6.57 mmol, 99.8% yield). ¹H NMR(DMSO-d₆, 500 MHz) δ ppm 2.20 (s, 6H), 2.46 (t, J=7 Hz, 2H), 3.12 (q,J=6 Hz, 2H), 4.79 (s, 2H), 5.21 (s, 2H), 5.91 (t, J=5 Hz, 1H), 6.28 (dd,J=9 Hz, J=1 Hz, 1H), 6.36 (t, J=2 Hz, 1H), 6.37-6.42 (m, 1H), 7.46 (s,1H), 7.64 (s, 1H); ESIMS found C₁₅H₂₀FN₅ m/z 290.1 (M+H).

Preparation of intermediate (LXXXIII) is depicted below in Scheme 15.

Step 1

To a solution of 3-bromo-5-fluorobenzaldehyde (LXXIX) (2.03 g, 10.01mmol) in DCE (50 mL) was added methanesulfonamide (1.43 g, 15.01 mmol)and TEA (2.79 mL, 20.02 mmol). NaBH(OAc)₃ (3.00 g, 14.13 mmol) was addedand stirred at room temperature overnight. The solvent was removed undervacuum and the residue was partitioned between EtOAc and water. Theorganic layer sparated and washed with water, brine, dried over MgSO₄and evaporated under vacuum to produceN-(3-bromo-5-fluorobenzyl)methanesulfonamide (LXXX) as a colorless oil(2.653 g, 9.40 mmol, 93.9% yield). ESIMS found C₈H₉BrFNO₂S m/z 282.0(M+H).

Step 2-4

Procedures can be found in Scheme 13, Steps 2-4.N-(3-(4,5-Diaminopyridin-3-yl)-5-fluorobenzyl)methanesulfonamide LXXXIIIwas isolated as a light tan solid (428.4 mg, 1.38 mmol, quantitativeyield). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm 2.92 (s, 3H), 4.24 (d, J=6.3 Hz,2H), 4.80 (s, 2H), 5.23 (s, 2H), 7.11-7.13 (m, 1H), 7.16-7.18 (m, 1H),7.22 (s, 1H), 7.47 (s, 1H), 7.64 (d, J=6.3 Hz, 1H), 7.68 (s, 1H); ESIMSfound C₁₃H₁₅FN₄O₂S m/z 311 (M+H).

Example 1

Preparation of compound (1) is depicted below in Scheme 16.

Step 1-2

A solution of5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde (II) (498mg, 1.4 mmol), bis(pinacolato)diboron (426 mg, 1.6 mmol), KOAc (412 mg,4.2 mmol) and dry DMF (10 mL) was purged with nitrogen. Pd(dppf)₂Cl₂ (68mg, 0.08 mmol) was added to the reaction and purged again with nitrogen.The solution was heated at 90° C. for 2 h. Once TLC showed thedisappearance of (II), the solution was cooled to room temperature. Tothis solution was added K₃PO₄ (446 mg, 2.1 mmol),N-(5-bromopyridin-3-yl)-3-methylbutanamide (XXVIII) (358 mg, 1.4 mmol),Pd(PPh₃)₄ (48 mg, 0.042 mmol) and water (2 mL). The solution was purgedwith nitrogen and heated at 90° C. for 4 h. The reaction was passedthrough a pad of Celite® and then concentrated under reduced pressure.The residue was suspended in water, sonicated, filtered and dried. Thecrude product was purified on a silica gel column (100% DCM→3:97MeOH:DCM) to giveN-(5-(3-formyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-3-methylbutanamide(LXXXIV) as an off white solid (239 mg, 0.59 mmol, 42% yield). ¹H NMR(DMSO-d₆, 500 MHz) δ ppm 0.96 (d, 6H), 1.60-1.67 (m, 1H), 1.75-1.84 (m,1H), 2.05-2.15 (m, 3H), 2.26 (d, 2H), 2.39-2.47 (m, 1H), 3.80-3.86 (m,1H), 3.89-3.93 (m, 1H), 6.13 (dd, 1H), 7.91 (dd, 1H), 8.06 (d, 1H), 8.36(s, 1H), 8.39 (s, 1H), 8.63 (d, 1H), 8.81 (d, 1H), 10.23 (s, 1H); ESIMSfound C₂₃H₂₆N₄O₃ m/z 407.3 (M+H).

Step 3-4

A solution ofN-(5-(3-formyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-3-methylbutanamide(LXXXIV) (52 mg, 0.127 mmol),5-(4-methylpiperazin-1-yl)pyridine-3,4-diamine (LVIII) (29 mg, 0.13mmol) and sulfur (45 mg, 0.13 mmol) in dry DMF (10 mL) was heated at140° C. overnight. The reaction was cooled and evaporated under vacuum.The viscous residue was dried overnight under vacuum. The solid waswashed with cold water and dried under vacuum. The crude product (LXXXV)was dissolved in DCM (5 mL) followed by Et₃SiH (48 μL, 0.30 mmol) andslowly addition of TFA (2.5 mL). The reaction was stirred until TLC (10%MeOH/DCM) showed the reaction was complete. The reaction was evaporatedunder vacuum and the residue was treated with water, sonicated and thenbasified with aq. ammonia. The solids were filtered, washed with coldwater and dried. The crude product was heated in EtOAc and filtered hotto remove impurities. The hot EtOAc solution was allowed to slowly coolto room temperature and filtered to give3-methyl-N-(5-(3-(7-(4-methylpiperazin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)butanamide1 as a pink solid (36 mg, 0.071 mmol, 59% yield). ¹H NMR (DMSO-d₆, 500MHz) δ ppm 0.97 (d, 6H), 2.13 (m, 1H), 2.27 (m, 4H), 3.45 (m, 4H), 6.70(s, 1H), 7.79 (dd, 2H), 8.36 (s, 1H), 8.62 (s, 1H), 8.65 (s, 1H), 8.66(s, 1H), 8.84 (s, 1H), 10.26 (s, 1H), 12.97 (s, 1H), 13.82 (s, 1H);ESIMS found for C₂₈H₃₁N₉O m/z 510.5 (M+H).

The following compounds were prepared in accordance with the proceduredescribed in the above Example 1.

N-(5-(3-(7-(4-methylpiperazin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)isobutyramide2

Brick red solid (35% yield). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm 1.16 (d,6H), 2.33 (brs, 3H), 2.58 (m, 4H), 2.64 (m, 1H), 3.49 (m, 4H), 6.71 (s,1H), 7.79 (dd, 2H), 8.38 (s, 1H), 8.62 (s, 1H), 8.66 (s, 2H), 8.86 (dd,1H), 10.23 (s, 1H), 12.99 (s, 1H), 13.83 (s, 1H); ESIMS found forC₂₇H₂₉N₉O m/z 496.4 (M+H).

N,N-dimethyl-1-(5-(3-(7-(4-methylpiperazin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methanamine3

Off white solid (63% yield). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm 2.22 (s,6H), 2.24 (s, 3H), 2.46 (m, 4H), 3.45 (m, 4H), 3.55 (s, 2H), 6.69 (s,1H), 7.81 (dd, 2H), 8.03 (s, 1H), 8.51 (d, 1H), 8.65 (s, 1H), 8.68 (s,1H), 8.84 (d, 1H), 12.95 (brs, 1H), 13.81 (brs, 1H); ESIMS found forC₂₆H₂₉N₉ m/z 468.3 (M+H).

7-(4-methylpiperazin-1-yl)-2-(5-(pyridin-3-yl)-1H-indazol-3-yl)-3H-imidazo[4,5-c]pyridine4

Light brown solid (51% yield). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm 2.24 (s,3H), 2.56-2.67 (m, 4H), 3.43-3.54 (m, 4H), 6.72 (s, 1H), 7.55 (dd, 1H),7.83 (dd, 2H), 8.16 (dd, 1H), 8.61 (dd, 1H), 8.66 (s, 1H), 8.70 (s, 1H),8.96 (d, 1H), 13.00 (brs, 1H), 13.82 (s, 1H); ESIMS found C₂₃H₂₂N₈ m/z411.1 (M+H).

4-(5-(3-(7-(4-methylpiperazin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)morpholine5

Off white solid (69% yield). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm 2.24 (s,3H), 2.46 (m, 4H), 3.36 (m, 4H), 3.45 (m, 4H), 3.80 (t, 4H), 6.69 (s,1H), 7.57 (s, 1H), 7.80 (dd, 2H), 8.35 (dd, 2H), 8.66 (d, 1H), 12.92(brs, 1H), 13.76 (brs, 1H); ESIMS found C₂₇H₂₉N₉O m/z 4.96.5 (M+H).

4-(2-(5-(pyridin-3-yl)-1H-indazol-3-yl)-3H-imidazo[4,5-c]pyridin-7-yl)morpholine6

Beige solid (65% yield). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm 3.41 (t, 4H),3.76 (t, 4H), 6.75 (brs, 1H), 7.56 (dd, 1H), 7.83 (dd, 2H), 8.17 (dd,1H), 8.62 (d, 1H), 8.66 (brs, 1H), 8.71 (s, 1H), 8.96 (s, 1H), 13.05(brs, 1H), 13.84 (s, 1H); ESIMS found C₂₂H₁₉N₇O m/z 398.0 (M+H).

2-(5-(5-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-indazol-3-yl)-3H-imidazo[4,5-c]pyridine 7

Off white solid (68% yield). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm 2.29 (s,3H), 2.57 (m, 4H), 3.35 (m, 4H), 7.52 (brs, 1H), 7.57 (t, 1H), 7.81 (dd,2H), 8.34 (m, 3H), 8.70 (s, 1H), 9.06 (brs, 1H), 13.45 (brs, 1H), 13.89(brs, 1H); ESIMS found C₂₃H₂₂N₈ m/z 410.9 (M+H).

N-(5-(3-(3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)isobutyramide9

Tan solid (63% yield). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm 1.16 (d, 6H),2.67 (sep, 1H), 7.53 (d, 1H), 7.79 (dd, 2H), 8.34 (d, 1H), 8.40, (s,1H), 8.63 (d, 1H), 8.70 (s, 1H), 8.87 (s, 1H), 9.06 (s, 1H), 10.27 (s,1H), 13.49 (s, 1H), 13.98 (s, 1H); ESIMS found C₂₂H₁₉N₇O m/z 3.98.0(M+H).

N-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-3-methylbutanamide10

White solid (98% yield). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm 0.98 (d, 6H),2.13 (m, 1H), 2.28 (d, 2H), 7.24 (t, 1H), 7.60 (dd, 1H), 7.84 (dd, 2H),8.27 (d, 1H), 8.38 (d, 1H), 8.49 (s, 1H), 8.66 (s, 1H), 8.77 (s, 2H),8.87 (d, 2H), 10.23 (s, 1H), 13.81 (brs, 1H), 14.05 (s, 1H); ESIMS foundC₂₉H₂₄FN₇O m/z 506.1 (M+H).

N-(5-(3-(7-(2-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-3-methylbutanamide11

White solid (37% yield). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm 0.98 (d, 6H),2.13 (m, 1H), 2.29 (d, 2H), 7.37-7.41 (m, 2H), 7.48-7.63 (m, 1H),7.77-7.84 (m, 2H), 8.15 (m, 1H), 8.30-8.45 (m, 1H), 8.51-8.60 (dd, 1H),8.73 (dd, 1H), 8.85 (m, 2H), 8.88 (s, 1H), 10.27 (m, 1H), 13.68 (brs,1H), 14.93 (s, 1H); ESIMS found C₂₉H₂₄FN₇O m/z 506.3 (M+H).

N-(5-(3-(7-(4-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-3-methylbutanamide12

White solid (50% yield). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm 0.98 (d, 6H),2.17 (m, 1H), 2.32 (d, 2H), 7.40 (m, 2H), 7.84 (s, 2H), 8.45 (m, 2H),8.58 (s, 1H), 8.67 (s, 2H), 8.72 (d, 1H), 8.83 (m, 2H), 10.30 (s, 1H),13.71 (brs, 1H), 14.02 (s, 1H); ESIMS found C₂₉H₂₄FN₇O m/z 506.1 (M+H).

7-(3-fluorophenyl)-2-(5-(pyridin-3-yl)-1H-indazol-3-yl)-3H-imidazo[4,5-c]pyridine 15

Brown solid (75% yield). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm 7.32 (td, 1H),7.65 (m, 1H), 7.61 (dd, 1H), 7.85 d, 1H), 7.92 (d, 1H), 8.20 (d, 2H),8.49 (d, 1H), 8.63 (dd, 1H), 8.78 (s, 1H), 8.88 (s, 1H), 8.94 (s, 1H),9.03 (1H), 13.82 (brs, 1H), 14.02 (s, 1H); ESIMS found C₂₄H₁₅FN₆ m/z407.3 (M+H).

1-(5-(3-(7-(5-fluoropyridin-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine16

Off white solid (60% yield). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm 2.36 (brs,6H), 3.69 (brs, 2H), 7.85 (d, 1H), 7.91 (d, 1H), 8.07 (s, 1H), 8.56 (s,1H), 8.67 (d, 1H), 8.83 (m, 3H), 8.92 (s, 2H), 9.49 (s, 1H), 13.86 (s,1H), 14.06 (s, 1H); ESIMS found C₂₆H₂₁FN₈ m/z 465.0 (M+H).

N-(5-(3-(7-(5-fluoropyridin-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)propionamide20

Brown solid (63% yield). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm 1.13 (t, 3H),2.41 (m, 2H), 7.81-7.87 (m, 2H), 8.45 (s, 1H), 8.65 (s, 2H), 8.78-8.93(m, 4H), 9.40 (s, 1H), 10.20 (s, 1H), 13.91 (brs, 1H), 14.02 (s, 1H);ESIMS found C₂₆H₁₉FN₈O m/z 479.1 (M+H).

N-(5-(3-(7-(3-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)propionamide24

Tan solid (37.5 mg). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm 1.14 (t, J=7.5 Hz,3H), 2.44 (q, J=7.5 Hz, 2H), 7.28 (t, J=8 Hz, 1H), 7.61 (q, J=8 Hz, 1H),7.84 (q, J=8.5 Hz, 2H), 8.23 (brs, 1H), 8.35 (brs, 1H), 8.50 (s, 1H),8.67 (s, 1H), 8.76 (s, 2H), 8.85 (s, 1H), 8.93 (brs, 1H), 10.24 (s, 1H),14.07 (s, 1H); ESIMS found C₂₇H₂₀FN₇O m/z 478.3 (M+H).

N-(5-(3-(7-(2-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)isobutyramide31

Beige solid (27.5 mg, 20.3% yield). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm 1.17(d, J=6.5 Hz, 6H), 2.68 (sex, J=7 Hz, 1H), 7.40-7.52 (m, 3H), 7.55-7.63(m, 2H), 7.84 (dd, J=9 Hz, J=1.5 Hz, 1H), 7.90 (d, J=8.5 Hz, 1H), 8.50(brs, 1H), 8.62 (s, 1H), 8.72 (s, 2H), 8.80 (brs, 1H), 10.27 (s, 1H),13.09 (brs, 1H), 14.29 (brs, 1H); ESIMS found C₂₈H₂₂FN₇O m/z 492.2(M+H).

N-(5-(3-(7-(3-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-2-phenylacetamide86

Beige solid (14.1 mg, 16.1% yield). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm 3.76(s, 2H), 7.18 (t, J=6.5 Hz, 1H), 7.27 (t, J=7.5 Hz, 1H), 7.29-7.42 (m,4H), 7.81 (d, J=7.5 Hz, 1H), 7.85 (d, J=8.5 Hz, 1H), 8.25 (d, J=7.5 Hz,1H), 8.36 (d, J=11 Hz, 1H), 8.50 (s, 1H), 8.66 (s, 1H), 8.76 (s, 1H),8.77 (s, 1H), 8.86 (d, J=3 Hz, 1H), 10.56 (s, 1H), 13.77 (s, 1H), 14.04(s, 1H); ESIMS found C₃₂H₂₂FN₇O m/z 540.5 (M+H).

1-(5-(3-(7-(3-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine89

Light brown solid (16.1 mg, 19.0% yield). ¹H NMR (DMSO-d₆, 500 MHz) δppm 2.30 (brs, 9H), 3.69 (brs, 2H), 7.31 (dt, J=2.5 Hz, J=8.5 Hz, 1H),7.61 (q, J=7.5 Hz, 1H), 7.85 (d, J=9 Hz, 1H), 7.91 (d, J=9 Hz, 1H), 8.08(brs, 1H), 8.23 (d, J=7.5 Hz, 1H), 8.32 (d, J=7 Hz, 1H), 8.40 (s, 1H),8.76 (s, 1H), 8.88 (d, J=7.5 Hz, 2H), 8.99 (s, 1H), 13.78 (brs, 1H),14.04 (brs, 1H); ESIMS found C₂₇H₂₂FN₇ m/z 463.9 (M+H).

N-(5-(3-(7-(3-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-3,3-dimethylbutanamide90

Light brown solid (10.5 mg, 5.9% yield). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm1.06 (s, 9H), 2.28 (s, 2H), 7.24 (dt, J=8.5 Hz, J=2 Hz, 1H), 7.59 (q,J=8 Hz, 1H), 7.81 (d, J=8.5 Hz, 1H), 7.86 (d, J=8.5 Hz, 1H), 8.26 (d,J=8 Hz, 1H), 8.38 (d, J=11 Hz, 1H), 8.49 (s, 1H), 8.66 (d, J=1.5 Hz,1H), 8.77 (dd, J=5.5 Hz, J=2 Hz, 2H), 8.87 (d, J=8 Hz, 2H), 10.17 (s,1H), 13.78 (s, 1H), 14.04 (s, 1H); ESIMS found C₃₀H₂₆FN₇O m/z 520.3(M+H).

N-(5-(3-(7-(3-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclopropanecarboxamide91

Yellow white solid (3.7 mg, 1.5% yield). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm0.92-0.97 (m, 2H), 1.01-1.06 (m, 2H), 1.86 (quin, J=4.5 Hz, 1H), 7.18(dt, J=8 Hz, J=2 Hz, 1H), 7.56 (q, J=8 Hz, 1H), 7.72 (d, J=8.5 Hz, 1H),7.76 (dd, J=8.5 Hz, J=1.5 Hz, 1H), 7.86-8.10 (m, 2H), 8.47 (t, J=2.5 Hz,1H), 8.50 (brs, 1H), 8.62 (d, J=2 Hz, 1H), 8.74 (d, J=2.5 Hz, 1H), 8.82(s, 2H); ESIMS found C₂₈H₂₀FN₇O m/z 489.8 (M+H).

N-(5-(3-(7-(3-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclohexanecarboxamide94

Light brown solid (27.6 mg, 29.0% yield). ¹H NMR (DMSO-d₆, 500 MHz) δppm 1.16-1.25 (m, 1H), 1.31 (q, J=12.5 Hz, 2H), 1.45 (q, J=12 Hz, 2H),1.67 (d, J=11.5 Hz, 1H), 1.79 (d, J=12.5 Hz, 2H), 1.88 (d, J=12 Hz, 2H),2.41 (dq, J=8 Hz, J=3 Hz, 1H), 7.22 (dt, J=8 Hz, J=2 Hz, 1H), 7.60 (q,J=7.5 Hz, 1H), 7.84 (q, J=9 Hz, 2H), 8.28 (d, 8 Hz, 1H), 8.39 (t, J=11Hz, 1H), 8.51 (s, 1H), 8.66 (d, J=1.5 Hz, 1H), 8.77 (s, 2H), 8.86 (d,J=6 Hz, 2H), 10.17 (s, 1H), 13.77 (s, 1H), 14.04 (s, 1H); ESIMS foundC₃₁H₂₆FN₇O m/z 532.2 (M+H).

5-(3-(7-(4-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-amine97

Tan solid (51.0 mg). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm 5.53 (brs, 2H),7.31-7.42 (m, 3H), 7.78 (q, J=8 Hz, 1H), 7.99 (d, J=2 Hz, 1H), 8.16 (s,1H), 8.23 (brs, 1H), 8.46 (brs, 2H), 8.67 (s, 1H), 8.84 (s, 2H), 13.72(brs, 1H), 14.02 (brs, 1H); ESIMS found C₂₄H₁₆FN₇ m/z 422.0 (M+H).

7-(4-Fluorophenyl)-2-(5-(4-methylpyridin-3-yl)-1H-indazol-3-yl)-3H-imidazo[4,5-c]pyridine99

Light brown solid (18.2 mg, 14.2% yield). ¹H NMR (DMSO-d₆, 500 MHz) δppm 2.39 (s, 3H), 7.36 (t, J=8.5 Hz, 2H), 7.50 (d, J=5 Hz, 1H), 7.62(dd, J=8.5 Hz, J=1.5 Hz, 1H), 7.85 (d, J=8.5 Hz, 1H), 8.28 (brs, 2H),8.54 (d, J=3.5 Hz, 2H), 8.58 (s, 1H), 8.71 (s, 1H), 9.06 (brs, 1H),14.21 (s, 1H); ESIMS found C₂₅H₁₇FN₆ m/z 421.0 (M+H).

N-(5-(3-(7-(4-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)pivalamide102

Tan solid (66.3 mg). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm 1.30 (s, 9H), 7.38(t, J=8.5 Hz, 2H), 7.85 (s, 2H), 8.48 (brs, 2H), 8.62 (brs, 1H), 8.67(s, 2H), 8.83 (s, 1H), 8.85 (brs, 1H), 8.90 (s, 1H), 9.62 (s, 1H), 13.76(brs, 1H), 14.03 (s, 1H); ESIMS found C₂₉H₂₄FN₇O m/z 506.1 (M+H).

N-(5-(3-(7-(4-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)benzamide104

Light brown solid (1.1 mg, 0.002 mmol, 2.4% yield). ¹H NMR (DMSO-d₆, 500MHz) δ ppm 7.39 (t, J=9 Hz, 2H), 7.59 (t, J=7.5 Hz, 2H), 7.65 (d, J=7Hz, 1H), 7.89 (s, 2H), 8.06 (dd, J=1 Hz, J=8.5 Hz, 2H), 8.47 (brs, 2H),8.70 (brs, 1H), 8.75 (s, 1H), 8.88 (s, 1H), 8.91 (brs, 1H), 8.99 (s,1H), 10.69 (s, 1H), 14.12 (s, 1H); ESIMS found C₃₁H₂₀FN₇O m/z 526.3(M+H).

7-(4-Fluorophenyl)-2-(5-(5-(pyrrolidin-1-ylmethyl)pyridin-3-yl)-1H-indazol-3-yl)-3H-imidazo[4,5-c]pyridine107

Brown solid (12.7 mg, 57% yield). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm 1.71(brs, 4H), 2.47-2.56 (m, 4H), 3.76 (s, 2H), 7.41 (t, J=9 Hz, 2H), 7.83(d, J=8.5 Hz, 1H), 7.93 (d, J=9 Hz, 1H), 8.07 (s, 1H), 8.45 (t, J=6 Hz,2H), 8.56 (s, 1H), 8.66 (s, 1H), 8.84 (s, 1H), 8.90 (s, 1H), 8.92 (s,1H), 13.72 (brs, 1H), 14.00 (brs, 1H); ESIMS found C₂₉H₂₄FN₇ m/z 490.2(M+H).

N-(5-(3-(7-(4-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclobutanecarboxamide111

Brown solid (4.1 mg, 0.008 mmol, 22.0% yield). ¹H NMR (DMSO-d₆, 500 MHz)δ ppm 1.25-1.36 (m, 1H), 1.43-1.53 (m, 1H), 1.77-1.88 (m, 1H), 1.93-2.02(m, 1H), 2.13-2.22 (m, 1H), 2.25-2.34 (m, 1H), 2.84-2.95 (m, 1H), 7.35(brs, 2H), 7.40 (t, J=9 Hz, 2H), 7.84 (s, 2H), 8.19 (brs, 1H), 8.47(brs, 1H), 8.63 (brs, 1H), 8.66 (d, J=1.5 Hz, 1H), 8.73 (brs, 1H), 8.84(brs, 1H), 10.17 (s, 1H), 13.74 (brs, 1H); ESIMS found C₂₉H₂₂FN₇O m/z504.1 (M+H).

5-(3-(7-(2-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)-N-isopropylpyridin-3-amine124

Tan solid (11.1 mg, 0.024 mmol). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm1.14-1.26 (m, 6H), 3.59-3.77 (m, 1H), 5.80-5.90 (m, 1H), 7.10, 7.20 (2rotamers, 1H), 7.32-7.43 (m, 2H), 7.48-7.59 (m, 1H), 7.77 (s, 2H),8.03-8.13 (m, 1H), 8.30, 8.49 (2 rotamers, 1H), 8.68, 8.69 (2 rotamers,1H), 8.88, 9.10 (2 rotamers, 1H), 13.66, 13.68 (2 rotamers, 1H), 13.87,13.94 (2 rotamers, 1H); ESIMS found C₂₇H₂₂FN₇ m/z 463.9 (M+H).

7-(2-Fluorophenyl)-2-(5-(5-(piperidin-1-ylmethyl)pyridin-3-yl)-1H-indazol-3-yl)-3H-imidazo[4,5-c]pyridine127

Brown solid (53.7 mg, 39% yield). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm1.36-1.57 (m, 6H), 2.42 (m, 4H), 3.61 (s, 2H), 7.35-7.46 (m, 2H),7.50-7.58 (m, 1H), 7.82 (d, J=9 Hz, 1H), 7.88 (d, J=7.5 Hz, 1H), 7.97(s, 1H), 8.16 (t, J=8 Hz, 1H), 8.52 (d, J=7.5 Hz, 2H), 8.79 (s, 1H),8.86 (s, 1H), 13.71 (s, 1H), 13.99 (s, 1H); ESIMS found C₃₀H₂₆FN₇ m/z504.3 (M+H).

7-(Pyridin-3-yl)-2-(5-(pyridin-3-yl)-1H-indazol-3-yl)-3H-imidazo[4,5-c]pyridine136

Light brown solid (35.1 mg, 51.5% yield). ¹H NMR (DMSO-d₆, 500 MHz) δppm 7.56-7.64 (m, 2H), 7.85 (d, J=8.5 Hz, 1H), 7.90 (d, J=10 Hz, 1H),8.19 (td, J=1.5 Hz, J=8 Hz, 1H), 8.64 (dd, J=4.5 Hz, J=1.5 Hz, 1H), 8.69(dd, J=5 Hz, J=1.5 Hz, 1H), 8.77 (brs, 2H), 8.86 (s, 1H), 8.95 (brs,1H), 9.01 (d, J=1.5 Hz, 1H), 9.52 (brs, 1H), 14.06 (s, 1H); ESIMS foundC₂₃H₁₅N₇ m/z 389.8 (M+H).

2-(5-(4-Methylpyridin-3-yl)-1H-indazol-3-yl)-7-(pyridin-4-yl)-3H-imidazo[4,5-c]pyridine154

Light yellow solid (2.7 mg, 3.0% yield). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm2.42 (s, 3H), 7.45 (d, J=5 Hz, 1H), 7.61 (d, J=9 Hz, 1H), 7.83 (d, J=8.5Hz, 1H), 8.36 (d, J=5.5 Hz, 2H), 8.50 (d, J=5.5 Hz, 1H), 8.56 (s, 1H),8.61 (s, 1H), 8.65 (d, J=5 Hz, 1H), 8.81 (s, 1H), 8.92 (s, 1H), 13.85(s, 1H), 14.05 (s, 1H); ESIMS found C₂₄H₁₇N₇ m/z 404.1 (M+H).

7-(Pyridin-4-yl)-2-(5-(5-(pyrrolidin-1-ylmethyl)pyridin-3-yl)-1H-indazol-3-yl)-3H-imidazo[4,5-c]pyridine163

Brown solid (9.7 mg, 70% yield). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm 1.73(brs, 4H), 2.51-2.62 (m, 4H), 3.76 (s, 2H), 7.85 (d, J=8.5 Hz, 1H), 7.94(d, J=9 Hz, 1H), 8.11 (s, 1H), 8.47 (d, J=4 Hz, 2H), 8.56 (s, 1H), 8.77(d, J=4 Hz, 2H), 8.85 (s, 1H), 8.93 (brs, 3H), 13.85 (brs, 1H), 14.04(brs, 1H); ESIMS found C₂₈H₂₄N₈ m/z 473.3 (M+H).

2-(5-(5-(Piperidin-1-ylmethyl)pyridin-3-yl)-1H-indazol-3-yl)-7-(pyridin-4-yl)-3H-imidazo[4,5-c]pyridine164

Brown solid (70 mg, 73% yield). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm 1.40(brs, 2H), 1.51 (brs, 4H), 2.43 (brs, 4H), 3.63 (brs, 2H), 7.85 (d,J=8.5 Hz, 1H), 7.92 (d, J=8.5 Hz, 1H), 8.08 (s, 1H), 8.46 (d, J=5.5 Hz,2H), 8.54 (s, 1H), 8.76 (d, J=5.5 Hz, 2H), 8.84 (s, 1H), 8.90-8.97 (m,3H), 13.85 (brs, 1H), 14.04 (brs, 1H); ESIMS found C₂₉H₂₆N₈ m/z 487.1(M+H).

N-(5-(3-(7-(Pyridin-4-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclopentanecarboxamide170

Tan solid (30.2 mg, 0.06 mmol). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm1.54-1.65 (m, 2H), 1.65-1.76 (m, 2H), 1.76-1.87 (m, 2H), 1.88-1.98 (m,2H), 2.88 (quin, J=8 Hz, 1H), 7.86 (s, 2H), 8.46 (d, J=4.5 Hz, 2H), 8.66(s, 1H), 8.68 (s, 1H), 8.70-8.77 (m, 3H), 8.86 (s, 1H), 8.88 (s, 1H),8.93 (s, 1H), 10.30 (s, 1H), 13.86 (brs, 1H), 14.06 (s, 1H); ESIMS foundC₂₉H₂₄N₈O m/z 501.2 (M+H).

1-Cyclopentyl-N-((5-(3-(7-(pyridin-4-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methyl)methanamine173

Brown solid (1.7 mg, 0.003 mmol, 2.5% yield). ¹H NMR (DMSO-d₆, 500 MHz)δ ppm 1.41-1.63 (m, 8H), 1.79 (brs, 1H), 3.01 (brs, 2H), 4.34 (brs, 2H),7.84-7.89 (m, 1H), 7.92 (d, J=5.5 Hz, 1H), 8.41 (s, 1H), 8.47 (d, J=6Hz, 2H), 8.75 (s, 1H), 8.76 (d, J=6 Hz, 2H), 8.86 (s, 1H), 8.94 (s, 1H),8.98 (s, 1H), 9.11 (s, 1H), 13.81 (brs, 1H), 14.11 (s, 1H); ESIMS foundC₃₀H₂₈N₈ m/z 501.3 (M+H).

N-(5-(3-(7-(Pyridin-2-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)propionamide174

Tan solid (40.1 mg). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm 1.15 (t, J=7.5 Hz,3H), 2.44 (q, J=7 Hz, 2H), 7.47 (brs, 1H), 7.89 (s, 2H), 8.03 (t, J=7.5Hz, 1H), 8.59 (brs, 1H), 8.69 (s, 1H), 8.75 (brs, 1H), 8.83 (brs, 1H),9.03 (brs, 1H), 9.21 (brs, 2H), 10.30 (s, 1H), 14.10 (s, 1H); ESIMSfound C₂₆H₂₀N₈O m/z 461.1 (M+H).

7-(Pyridin-2-yl)-2-(5-(pyridin-3-yl)-1H-indazol-3-yl)-3H-imidazo[4,5-c]pyridine177

White solid (32.4 mg, 41.6% yield). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm 7.51(dd, J=7 Hz, J=5 Hz, 1H), 7.61 (dd, J=7.5 Hz, J=5 Hz, 1H), 7.87 (d,J=8.5 Hz, 1H), 7.92 (d, J=9 Hz, 1H), 8.02 (t, J=7.5 Hz, 1H), 8.23 (d,J=8 Hz, 1H), 8.65 (d, J=4 Hz, 1H), 8.84 (brs, 1H), 8.90 (brs, 1H), 9.05(brs, 2H), 9.20 (brs, 2H), 14.09 (s, 1H); ESIMS found C₂₃H₁₅N₇ m/z 390.2(M+H).

N,N-Dimethyl-1-(5-(3-(7-(pyridin-2-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methanamine186

Light brown solid (18.4 mg, 25.8% yield). ¹H NMR (DMSO-d₆, 500 MHz) δppm 2.84 (s, 6H), 4.47 (s, 2H), 7.52 (dd, J=6.5 Hz, J=4.5 Hz, 1H), 7.92(s, 2H), 8.02 (t, J=7 Hz, 1H), 8.38 (s, 1H), 8.73 (s, 1H), 8.80-9.26 (m,6H), 14.17 (brs, 1H); ESIMS found C₂₆H₂₂N₈ m/z 447.0 (M+H).

3-Methyl-N-(5-(3-(7-(piperidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)butanamide199

Brown solid (22.7 mg, 22.2% yield). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm 0.98(d, J=6.5 Hz, 6H), 1.52-1.64 (m, 6H), 2.13 (sep, J=7 Hz, 1H), 2.28 (d,J=7.5 Hz, 2H), 3.38-3.52 (m, 4H), 6.67 (s, 1H), 7.79 (s, 2H), 8.36 (d,J=2.5 Hz, 1H), 8.63 (dd, J=5 Hz, J=2 Hz, 2H), 8.66 (s, 1H), 8.85 (d, J=2Hz, 1H), 10.26 (s, 1H), 12.88 (s, 1H), 13.80 (s, 1H); ESIMS foundC₂₈H₃₀N₈O m/z 495.4 (M+H).

2-(5-(4-Methylpyridin-3-yl)-1H-indazol-3-yl)-7-(piperidin-1-yl)-3H-imidazo[4,5-c]pyridine202

White solid (1.5 mg, 1.1% yield). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm 1.65(brs, 6H), 2.38 (s, 3H), 3.51 (brs, 4H), 7.02 (brs, 1H), 7.59 (dd, J=9Hz, J=1.5 Hz, 1H), 7.65 (d, J=5 Hz, 1H), 7.85 (d, J=8.5 Hz, 1H), 8.43(s, 1H), 8.64 (brs, 2H), 8.71 (brs, 1H), 13.76 (brs, 1H), 14.21 (s, 1H);ESIMS found C₂₄H₂₃N₇ m/z 410.1 (M+H).

N-(5-(3-(7-(Piperidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)pivalamide205

Tan solid (66.5 mg). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm 1.29 (s, 9H), 1.60(brs, 6H), 3.48 (brs, 4H), 6.67 (s, 1H), 7.80 (s, 2H), 8.41 (t, J=2 Hz,1H), 8.63 (d, J=1.5 Hz, 1H), 8.64 (s, 1H), 8.67 (s, 1H), 8.97 (d, J=2Hz, 1H), 9.59 (s, 1H), 12.89 (s, 1H), 13.81 (s, 1H); ESIMS foundC₂₈H₃₀N₈O m/z 495.5 (M+H).

7-(Piperidin-1-yl)-2-(5-(5-(pyrrolidin-1-ylmethyl)pyridin-3-yl)-1H-indazol-3-yl)-3H-imidazo[4,5-c]pyridine211

Brown solid (17.1 mg, 53% yield). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm 1.61(brs, 6H), 1.74 (brs, 4H), 2.48-2.56 (m, 4H), 3.48 (brs, 4H), 3.75 (s,2H), 6.67 (s, 1H), 7.81 (q, J=9.5 Hz, 2H), 8.04 (s, 1H), 8.53 (s, 1H),8.63 (s, 1H), 8.68 (s, 1H), 8.84 (s, 1H), 12.88 (brs, 1H), 13.79 (brs,1H); ESIMS found C₂₈H₃₀N₈ m/z 479.3 (M+H).

N-(5-(3-(7-(Piperidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)butyramide214

Brown solid (33.2 mg, 0.069 mmol). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm 0.96(t, J=7.5 Hz, 3H), 1.61 (brs, 6H), 1.66 (sex, J=7.5 Hz, 2H), 2.38 (t,J=7.5 Hz, 2H), 3.48 (brs, 4H), 6.67 (s, 1H), 7.79 (s, 2H), 8.36 (s, 1H),8.62 (s, 1H), 8.63 (s, 1H), 8.66 (s, 1H), 8.85 (d, J=1.5 Hz, 1H), 10.27(s, 1H), 12.88 (s, 1H), 13.80 (s, 1H); ESIMS found C₂₇H₂₈N₈O m/z 481.0(M+H).

N-(5-(3-(7-(Piperidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclobutanecarboxamide217

Beige solid (12 mg, 0.024 mmol, 46.9% yield). ¹H NMR (DMSO-d₆, 500 MHz)δ ppm 1.61 (brs, 6H), 1.80-1.88 (m, 1H), 1.93-2.04 (m, 1H), 2.11-2.21(m, 2H), 2.22-2.33 (m, 2H), 3.26-3.32 (m, 1H), 3.48 (brs, 4H), 6.67 (s,1H), 7.79 (s, 2H), 8.37 (d, J=2 Hz, 1H), 8.62 (d, J=2 Hz, 1H), 8.64 (s,1H), 8.66 (s, 1H), 8.87 (d, J=2 Hz, 1H), 10.12 (s, 1H), 12.88 (s, 1H),13.80 (s, 1H); ESIMS found C₂₈H₂₈N₈O m/z 493.2 (M+H).

5-(3-(7-(4-Methylpiperazin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-amine247

Tan solid (9.6 mg). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm 2.36 (s, 3H),2.44-2.56 (m, 4H), 3.46 (brs, 4H), 5.50 (s, 2H), 6.70 (s, 1H), 7.26 (t,J=2 Hz, 1H), 7.65-7.76 (m, 2H), 7.96 (d, J=2 Hz, 1H), 8.09 (d, J=1.5 Hz,1H), 8.62 (s, 1H), 8.65 (s, 1H), 12.95 (s, 1H), 13.76 (s, 1H); ESIMSfound C₂₃H₂₃N₉ m/z 426.4 (M+H).

N-(5-(3-(7-(4-Methylpiperazin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-2-phenylacetamide252

Beige solid (7.0 mg, 4.5% yield). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm 2.24(s, 3H), 2.46 (brs, 5H), 3.45 (brs, 3H), 3.74 (s, 2H), 6.69 (s, 1H),7.27 (t, J=5.5 Hz, 1H), 7.32-7.41 (m, 4H), 7.79 (s, 2H), 8.36 (s, 1H),8.64 (s, 2H), 8.66 (s, 1H), 8.86 (d, J=2.5 Hz, 1H), 10.58 (s, 1H), 12.96(s, 1H), 13.82 (s, 1H); ESIMS found C₃₁H₂₉N₉O m/z 544.2 (M+H).

3,3-Dimethyl-N-(5-(3-(7-(4-methylpiperazin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)butanamide257

White solid (65.7 mg, 23.0% yield). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm 1.06(s, 9H), 2.24 (s, 4H), 2.28 (s, 2H), 2.46 (brs, 4H), 3.45 (brs, 3H),6.69 (s, 1H), 7.79 (ABq, J=10.5 Hz, 2H), 8.37 (t, J=2 Hz, 1H), 8.65 (dt,J=9.5 Hz, J=2 Hz, 3H), 8.85 (d, J=2 Hz, 1H), 10.2 (s, 1H), 12.97 (s,1H), 13.82 (s, 1H); ESIMS found C₂₉H₃₃N₉O m/z 524.3 (M+H).

N-(5-(3-(7-(4-Methylpiperazin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclopropanecarboxamide260

Brown solid (30.0 mg, 15.1% yield). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm0.83-0.91 (m, 4H), 1.80-1.87 (m, 1H), 2.24 (s, 3H), 2.47 (brs, 5H), 3.45(brs, 3H), 6.69 (s, 1H), 7.78 (ABq, J=9 Hz, 2H), 8.36 (d, J=2 Hz, 1H),8.62 (d, J=2 Hz, 1H), 8.66 (d, J=2 Hz, 2H), 8.84 (d, J=2 Hz, 1H), 10.60(s, 1H), 12.96 (s, 1H), 13.82 (s, 1H); ESIMS found C₂₇H₂₇N₉O m/z 494.4(M+H).

N-(5-(3-(7-(4-Methylpiperazin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclohexanecarboxamide263

Brown solid (1.7 mg, 2.2% yield). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm1.16-1.26 (m, 5H), 1.31 (q, J=12.5 Hz, 2H), 1.45 (q, J=9.5 Hz, 3H), 1.67(d, J=12 Hz, 1H), 1.78 (d, J=18 Hz, 2H), 1.87 (d, J=12 Hz, 2H),2.23-2.51 (m, 6H), 3.44 (brs, 3H), 6.70 (1H), 7.79 (ABq, J=13.5 Hz, 2H),8.38 (s, 1H), 8.60 (d, J=2 Hz, 1H), 8.64 (d, J=4 Hz, 2H), 8.84 (d, J=2Hz, 1H), 10.20 (s, 1H), 12.99 (brs, 1H), 13.82 (s, 1H); ESIMS foundC₃₀H₃₃N₉O m/z 536.3 (M+H).

5-(3-(3H-Imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-amine 268

Tan solid (81.6 mg). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm 7.54 (brs, 1H),7.81 (dd, J=8.5 Hz, J=1.5 Hz, 1H), 7.89 (d, J=9 Hz, 1H), 8.02 (d, J=2.5Hz, 2H), 8.24 (s, 1H), 8.56 (d, J=6 Hz, 1H), 8.68 (s, 1H), 14.31 (s,1H); ESIMS found C₁₈H₁₃N₇ m/z 328.1 (M+H).

N-(5-(3-(3H-Imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-2-phenylacetamide274

Beige solid (19.0 mg, 10.3% yield). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm 3.74(s, 2H), 7.27 (t, J=7 Hz, 1H), 7.32-7.40 (m, 4H), 7.52 (d, J=5.5 Hz,1H), 7.81 (ABq, J=11.5 Hz, 2H), 8.34 (d, J=5.5 Hz, 1H), 8.38 (t, J=2 Hz,1H), 8.65 (d, J=2 Hz, 1H), 8.86 (d, J=1.5 Hz, 1H), 9.05 (s, 1H), 10.58(s, 1H), 13.48 (brs, 1H), 13.95 (brs, 1H); ESIMS found C₂₆H₁₉N₇O m/z446.3 (M+H).

N-(5-(3-(3H-Imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)benzamide275

Light brown solid (2.1 mg, 0.005 mmol, 3.1% yield). ¹H NMR (DMSO-d₆, 500MHz) δ ppm 7.57 (dt, J=2 Hz, J=7.5 Hz, 2H), 7.64 (dd, J=2.5 Hz, J=7.5Hz, 2H), 7.86 (s, 2H), 8.05 (dd, J=1.5 Hz, J=8.5 Hz, 2H), 8.35 (d, J=5.5Hz, 1H), 8.57 (dt, J=2 Hz, J=4 Hz, 1H), 8.72 (d, J=2 Hz, 1H), 8.76 (s,1H), 9.04 (d, J=2 Hz, 1H), 9.09 (d, J=2 Hz, 1H), 10.64 (s, 1H), 14.02(s, 1H); ESIMS found C₂₅H₁₇N₇O m/z 432.3 (M+H).

N-(5-(3-(3H-Imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-3,3-dimethylbutanamide280

Light brown solid (12.2 mg, 10.9% yield). ¹H NMR (DMSO-d₆, 500 MHz) δppm 1.07 (s, 9H), 2.29 (s, 2H), 7.85 (dd, J=9 Hz, J=1.5 Hz, 1H), 7.92(d, J=8.5 Hz, 1H), 8.06 (brs, 1H), 8.49 (s, 1H), 8.62 (d, J=6.5 Hz, 1H),8.67 (dd, J=7 Hz, J=1.5 Hz, 2H), 8.82 (d, J=1.5 Hz, 1H), 9.58 (brs, 1H),10.28 (s, 1H), 14.35 (s, 1H), 14.78 (brs, 1H); ESIMS found C₂₄H₂₃N₇O m/z426.1 (M+H).

N-(5-(3-(3H-Imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclopropanecarboxamide283

Yellow white solid (5.7 mg, 2.3% yield). ¹H NMR (CD₃OD, 500 MHz) δ ppm0.91-0.96 (m, 2H), 1.02-1.07 (m, 2H), 1.86 (quin, J=3.5 Hz, 1H), 7.21(sd, J=1.5 Hz, 1H), 7.69 (t, J=1.5 Hz, 1H), 7.73 (d, J=8.5 Hz, 1H), 7.78(dd, J=7.5 Hz, J=1.5 Hz, 1H), 8.50 (s, 1H), 8.59 (t, J=2 Hz, 1H), 8.65(d, J=2 Hz, 2H), 8.71 (d, J=2 Hz, 2H), 8.84 (s, 1H); ESIMS foundC₂₂H₁₇N₇O m/z 396.3 (M+H).

N-(5-(3-(3H-Imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclohexanecarboxamide286

Light brown solid (31.2 mg, 13.3% yield). ¹H NMR (DMSO-d₆, 500 MHz) δppm 1.16-1.34 (m, 3H), 1.45 (dq, J=12.5 Hz, J=3 Hz, 2H), 1.67 (d, J=17Hz, 1H), 1.79 (d, J=13 Hz, 2H), 1.87 (d, J=12.5 Hz, 2H), 2.41 (t ofquin, J=11.5 Hz, J=3.5 Hz, 1H), 7.53 (brs, 1H), 7.82 (dq, J=9 Hz, J=1.5Hz, 2H), 8.34 (d, 5 Hz, 1H), 8.40 (t, J=2 Hz, 1H), 8.62 (d, J=2 Hz, 1H),8.70 (s, 1H), 8.85 (d, J=2 Hz, 1H), 9.07 (brs, 1H), 10.21 (s, 1H), 13.51(brs, 1H), 13.99 (s, 1H); ESIMS found C₂₅H₂₃N₇O m/z 438.0 (M+H).

N-(5-(3-(7-(Thiophen-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)propionamide289

Tan solid (24.9 mg). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm 1.16 (t, J=7.5 Hz,3H), 2.46 (q, J=7.5 Hz, 2H), 7.76 (dd, J=4.5 Hz, J=3 Hz, 1H), 7.88 (s,2H), 8.15 (brs, 1H), 8.65 (brs, 1H), 8.69 (s, 1H), 8.71 (s, 1H), 8.78(brs, 1H), 8.82-8.93 (m, 3H), 10.30 (s, 1H), 14.13 (s, 1H); ESIMS foundC₂₅H₁₉N₇OS m/z 466.2 (M+H).

5-(3-(7-(Thiophen-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-amine291

Tan (11.9 mg). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm 5.49 (s, 2H), 7.31 (s,1H), 7.70-7.83 (m, 3H), 7.99 (s, 1H), 8.17 (s, 1H), 8.22 (d, J=4.5 Hz,1H), 8.74 (s, 1H), 8.78 (s, 1H), 8.82 (s, 1H), 8.83 (s, 1H), 13.67 (s,1H), 13.97 (s, 1H); ESIMS found C₂₂H₁₅N₇S m/z 410.1 (M+H).

2-(5-(4-Methylpyridin-3-yl)-1H-indazol-3-yl)-7-(thiophen-3-yl)-3H-imidazo[4,5-c]pyridine293

Light brown solid (36.0 mg, 35.0% yield). ¹H NMR (DMSO-d₆, 500 MHz) δppm 2.47 (s, 3H), 7.66 (dd, J=9.5 Hz, J=5.5 Hz, 1H), 7.68 (d, J=1.5 Hz,1H), 7.80 (q, J=3 Hz, 1H), 7.91 (d, J=8.5 Hz, 1H), 8.16 (brs, 1H),8.56-8.64 (m, 2H), 8.70 (s, 1H), 8.82 (brs, 1H), 8.96 (s, 1H), 9.10 (s,1H), 14.41 (s, 1H); ESIMS found C₂₃H₁₆N₆S m/z 409.4 (M+H).

N,N-Dimethyl-5-(3-(7-(thiophen-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-amine295

Tan solid (28.8 mg, 0.066 mmol). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm 3.09(s, 6H), 7.43 (s, 1H), 7.73 (dd, J=4.5 Hz, J=7.5 Hz, 2H), 7.83 (d, J=8.5Hz, 1H), 7.90 (dd, J=1.5 Hz, J=9 Hz, 1H), 8.17 (brs, 1H), 8.19 (d, J=3Hz, 1H), 8.32 (s, 1H), 8.80 (brs, 1H), 8.82 (s, 1H), 8.87 (s, 1H), 13.81(brs, 1H), 14.02 (s, 1H); ESIMS found C₂₄H₁₉N₇S m/z 438.1 (M+H).

N,N-Dimethyl-1-(5-(3-(7-(thiophen-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methanamine301

Brown solid (45 mg, 43.3% yield). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm 2.24(s, 6H), 3.59 (d, J=3 Hz, 2H), 7.75 (dd, J=10 Hz, J=3 Hz, 1H), 7.85 (d,J=8.5 Hz, 1H), 7.93 (d, J=10.5 Hz, 1H), 8.09 (s, 1H), 8.20 (d, J=5 Hz,1H), 8.54 (ABq, J=10.5 Hz, 1H), 8.78 (s, 1H), 8.79 (s, 1H), 8.82 (s,1H), 8.91 (s, 1H), 8.94 (d, J=2 Hz, 1H), 13.69 (s, 1H), 14.01 (s, 1H);ESIMS found C₂₅H₂₁N₇S m/z 452.0 (M+H).

2-(5-(5-(Piperidin-1-ylmethyl)pyridin-3-yl)-1H-indazol-3-yl)-7-(thiophen-3-yl)-3H-imidazo[4,5-c]pyridine303

Brown solid (92.8 mg, 52% yield). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm 1.39(brs, 2H), 1.51 (brs, 4H), 2.43 (brs, 4H), 3.64 (s, 2H), 7.75 (t, J=4.5Hz, 1H), 7.85 (d, J=8 Hz, 1H), 7.92 (d, J=9 Hz, 1H), 8.08 (s, 1H), 8.19(d, J=5 Hz, 1H), 8.54 (s, 1H), 8.79 (s, 2H), 8.81 (s, 1H), 8.92 (s, 2H),13.69 (brs, 1H), 14.01 (brs, 1H); ESIMS found C₂₈H₂₅N₇S m/z 492.3 (M+H).

3,3-Dimethyl-N-(5-(3-(7-(thiophen-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)butanamide304

Brown solid (15 mg, 26.2% yield). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm 1.07(s, 9H), 2.32 (s, 2H), 7.84 (dt, J=3 Hz, J=5 Hz, 1H), 7.90 (d, J=9 Hz,1H), 7.94 (d, J=8.5 Hz, 1H), 8.23 (brs, 1H), 8.66 (brs, 1H), 8.73 (s,1H), 8.76 (s, 1H), 8.84 (s, 1H), 8.94 (brs, 1H), 9.00 (brs, 1H), 9.11(brs, 1H), 10.30 (s, 1H), 14.42 (s, 1H), 14.93 (brs, 1H); ESIMS foundC₂₈H₂₅N₇OS m/z 508.2 (M+H).

1-Cyclopentyl-N-((5-(3-(7-(thiophen-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methyl)methanamine311

Light brown solid (4.9 mg, 0.01 mmol, 5.4% yield). ¹H NMR (DMSO-d₆, 500MHz) δ ppm 1.13-1.26 (m, 2H), 1.39-1.56 (m, 4H), 1.70 (brs, 2H), 2.01(t, J=7.5 Hz, 1H), 3.92 (s, 2H), 7.76 (dd, J=5 Hz, J=3 Hz, 1H), 7.85 (d,J=8.5 Hz, 1H), 7.92 (d, J=8.5 Hz, 1H), 8.19 (brs, 1H), 8.22 (d, J=4.5Hz, 1H), 8.59 (s, 1H), 8.79 (s, 2H), 8.82 (s, 1H), 8.92 (s, 1H), 8.95(s, 1H), 14.01 (brs, 1H); ESIMS found C₂₉H₂₇N₇S m/z 506.0 (M+H).

7-(Furan-3-yl)-2-(5-(pyridin-3-yl)-1H-indazol-3-yl)-3H-imidazo[4,5-c]pyridine315

Brown solid (68 mg, 77.5% yield). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm 7.44(d, J=1.5 Hz, 1H), 7.59 (dd, J=8 Hz, J=5 Hz, 1H), 7.87 (q, J=9 Hz, 2H),7.89 (s, 1H), 8.21 (dd, J=11 Hz, J=2 Hz, 1H), 8.63 (dd, J=9.5 Hz, J=1.5Hz, 1H), 8.71 (s, 1H), 8.76 (s, 1H), 8.86 (d, J=10 Hz, 2H), 9.03 (d,J=2.5 Hz, 1H), 13.65 (s, 1H), 14.01 (s, 1H); ESIMS found C₂₂H₁₄N₆O m/z379.1 (M+H).

N-(5-(3-(7-(Furan-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)pivalamide319

Tan solid (42.2 mg). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm 1.30 (s, 9H), 7.83(s, 1H), 7.86 (s, 2H), 8.59 (s, 1H), 8.71 (s, 2H), 8.77 (s, 1H), 8.83(s, 1H), 8.87 (s, 1H), 8.91 (d, J=2 Hz, 1H), 9.59 (s, 1H), 13.68 (brs,1H), 14.02 (s, 1H); ESIMS found C₂₇H₂₃N₇O₂ m/z 478.3 (M+H).

N-(5-(3-(7-(Furan-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-2-phenylacetamide321

Beige solid (12.6 mg, 7.3% yield). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm 3.76(s, 2H), 7.27 (t, J=7 Hz, 1H), 7.30-7.40 (m, 4H), 7.45 (s, 1H), 7.77 (s,1H), 7.84 (ABq, J=11.5 Hz, 2H), 8.57 (s, 1H), 8.71 (s, 2H), 8.76 (s,2H), 8.79 (s, 1H), 8.83 (s, 1H), 10.58 (s, 1H), 13.65 (s, 1H), 14.02 (s,1H); ESIMS found C₃₀H₂₁N₇O₂ m/z 512.1 (M+H).

N-(5-(3-(7-(Furan-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)pentanamide329

Brown solid (70.0 mg, 0.15 mmol, 7.3% yield). ¹H NMR (DMSO-d₆, 500 MHz)δ ppm 0.92 (t, J=7.5 Hz, 3H), 1.37 (sex, J=7.5 Hz, 2H), 1.63 (quin,J=7.5 Hz, 2H), 2.41 (t, J=7.5 Hz, 2H), 7.49 (brs, 1H), 7.82-7.93 (m,3H), 8.60 (s, 1H), 8.70 (s, 1H), 8.73 (s, 1H), 8.82 (s, 2H), 8.88 (s,1H), 8.96 (brs, 1H), 10.30 (s, 1H), 14.25 (s, 1H); ESIMS foundC₂₇H₂₃N₇O₂ m/z 478.3 (M+H).

N-(5-(3-(7-(Furan-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclopropanecarboxamide330

Light brown solid (10.6 mg, 4.2% yield). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm0.82-0.86 (m, 4H), 1.86 (quin, J=5.5 Hz, 1H), 7.49 (brs, 1H), 7.84-7.92(m, 3H), 8.64 (brs, 1H), 8.71 (d, J=7.5 Hz, 2H), 8.83 (d, J=9 Hz, 2H),8.89 (s, 1H), 8.98 (brs, 1H), 10.64 (s, 1H), 14.28 (s, 1H); ESIMS foundC₂₆H₁₉N₇O₂ m/z 461.9 (M+H).

N-(5-(3-(7-(Furan-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclohexanecarboxamide333

Brown solid (9.7 mg, 3.8% yield). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm1.14-1.36 (m, 3H), 1.46 (dq, J=12.5 Hz, J=2.5 Hz, 2H), 1.49 (dq, J=12.5Hz, J=2.5 Hz, 2H), 1.67 (d, J=12.5 Hz, 1H), 1.79 (d, J=13 Hz, 1H), 1.89(d, J=12 Hz, 2H), 2.00 (d, J=10 Hz, 2H), 7.44 (brs, 1H), 7.80-7.87 (m,3H), 8.57 (brs, 1H), 8.64-8.86 (m, 7H), 10.20 (s, 1H), 13.75 (brs, 1H),14.04 (s, 1H); ESIMS found C₂₉H₂₅N₇O₂ m/z 504.3 (M+H).

2-(5-(5-((3,3-Difluoropyrrolidin-1-yl)methyl)pyridin-3-yl)-1H-indazol-3-yl)-7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridine336

Light brown solid (71.2 mg, 82.5% yield). ¹H NMR (DMSO-d₆, 500 MHz) δppm 2.26 (sep, J=7 Hz, 2H), 2.76 (t, J=7 Hz, 2H), 2.95 (t, J=13 Hz, 2H),3.79 (s, 2H), 7.30 (dt, J=8.5 Hz, J=2 Hz, 1H), 7.60 (q, J=7.5 Hz, 1H),7.85 (d, J=9 Hz, 1H), 7.91 (d, J=8.5 Hz, 1H), 8.06 (s, 1H), 8.22 (d,J=7.5 Hz, 1H), 8.42 (d, J=11.5 Hz, 1H), 8.57 (s, 1H), 8.76 (s, 1H), 8.87(s, 1H), 8.89 (s, 1H), 8.93 (d, J=2 Hz, 1H), 13.77 (s, 1H), 14.03 (s,1H); ESIMS found C₂₉H₂₂F₃N₇ m/z 526.2 (M+H).

2-(5-(5-((3,3-Difluoropyrrolidin-1-yl)methyl)pyridin-3-yl)-1H-indazol-3-yl)-7-(pyridin-3-yl)-3H-imidazo[4,5-c]pyridine339

Brown solid (67.2 mg, 87.2% yield). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm 2.27(sep, J=7 Hz, 2H), 2.79 (t, J=7 Hz, 2H), 2.98 (t, J=13 Hz, 2H), 3.83 (s,2H), 7.60 (dd, J=7.5, J=4.5 Hz, 1H), 7.84 (d, J=8.5 Hz, 1H), 7.92 (d,J=8.5 Hz, 1H), 8.08 (s, 1H), 8.57 (s, 1H), 8.67 (d, J=4 Hz, 1H), 8.75(brs, 2H), 8.89 (s, 2H), 8.93 (s, 1H), 9.59 (s, 1H), 13.79 (s, 1H),14.02 (s, 1H); ESIMS found C₂₈H₂₂F₂N₈ m/z 509.3 (M+H).

2-(5-(5-((3,3-Difluoropyrrolidin-1-yl)methyl)pyridin-3-yl)-1H-indazol-3-yl)-7-(piperidin-1-yl)-3H-imidazo[4,5-c]pyridine342

Brown solid (50.4 mg, 42.1% yield). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm 1.60(brs, 6H), 2.28 (sep, J=7 Hz, 2H), 2.78 (t, J=7 Hz, 2H), 2.96 (t, J=13Hz, 2H), 3.42 (brs, 1H), 3.48 (brs, 3H), 3.80 (s, 2H), 6.67 (s, 1H),7.76-7.86 (m, 2H), 8.06 (s, 1H), 8.54 (s, 1H), 8.62 (s, 1H), 8.70 (s,1H), 8.86 (d, J=2 Hz, 1H), 12.88 (s, 1H), 13.79 (s, 1H); ESIMS foundC₂₈H₂₈F₂N₈ m/z 515.4 (M+H).

2-(5-(5-((3,3-Difluoropyrrolidin-1-yl)methyl)pyridin-3-yl)-1H-indazol-3-yl)-7-(thiophen-3-yl)-3H-imidazo[4,5-c]pyridine346

Brown solid (73.9 mg, 96.8% yield). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm 2.28(sep, J=7 Hz, 2H), 2.79 (t, J=7 Hz, 2H), 2.98 (t, J=13 Hz, 2H), 3.82 (s,2H), 7.75 (dd, J=5 Hz, J=3 Hz, 1H), 7.85 (d, J=9 Hz, 1H), 7.92 (d, J=8.5Hz, 1H), 8.12 (s, 1H), 8.20 (d, J=4.5 Hz, 1H), 8.57 (s, 1H), 8.79 (s,2H), 8.82 (s, 1H), 8.93 (s, 1H), 8.96 (s, 1H), 13.69 (s, 1H), 14.01 (s,1H); ESIMS found C₂₇H₂₁F₂N₇S m/z 514.4 (M+H).

N-(5-(3-(7-(3-(2-(Dimethylamino)ethylamino)-5-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-3-methylbutanamide349

Light brown solid (17.8 mg, 0.03 mmol, 50.7% yield). ¹H NMR (DMSO-d₆,500 MHz) δ ppm 0.97 (d, J=6.5 Hz, 6H), 2.09 (s, 7H), 2.26 (d, J=7 Hz,2H), 2.31 (brs, 2H), 3.11 (t, J=6 Hz, 2H), 5.79 (s, 1H), 6.44 (d, J=11Hz, 1H), 7.37 (s, 1H), 7.41 (d, J=9.5 Hz, 1H), 7.77 (d, J=9 Hz, 1H),7.85 (d, J=8.5 Hz, 1H), 8.36 (s, 1H), 8.63 (s, 2H), 8.83 (s, 2H), 10.19(s, 1H), 13.68 (brs, 1H), 14.01 (s, 1H); ESIMS found C₃₃H₃₄FN₉O m/z592.3 (M+H).

N-(5-(3-(7-(3-Fluoro-5-(methylsulfonamidomethyl)phenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-3-methylbutanamide373

Light brown solid (13.8 mg, 0.023 mmol, 20.9% yield). ¹H NMR (DMSO-d₆,500 MHz) δ ppm 0.97 (d, J=6.5 Hz, 6H), 2.11 (non, J=7.5 Hz, 1H), 2.27(d, J=7 Hz, 2H), 2.89 (s, 3H), 4.29 (d, J=6 Hz, 2H), 7.24 (d, J=8.5 Hz,1H), 7.71 (t, J=6 Hz, 1H), 7.80 (d, J=9 Hz, 1H), 7.87 (d, J=8.5 Hz, 1H),8.12 (s, 1H), 8.39 (d, J=10.5 Hz, 1H), 8.44 (s, 1H), 8.67 (s, 1H), 8.77(s, 1H), 8.78 (s, 1H), 8.85 (s, 1H), 8.88 (s, 1H), 10.20 (s, 1H), 13.80(s, 1H), 14.05 (s, 1H); ESIMS found C₃₁H₂₉FN₈O₃S m/z 613.1 (M+H).

3-Methyl-N-(5-(3-(7-(thiophen-2-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)butanamide397

Light brown solid (79.8 mg, 0.16 mmol, 62.2% yield). ¹H NMR (DMSO-d₆,500 MHz) δ ppm 0.98 (d, J=6.5 Hz, 6H), 2.15 (non, J=7 Hz, 1H), 2.31 (d,J=7.5 Hz, 2H), 7.26 (dd, J=5 Hz, J=3.5 Hz, 1H), 7.66 (d, J=5 Hz, 1H),7.86 (s, 2H), 8.23 (brs, 1H), 8.61 (s, 1H), 8.70 (d, J=1.5 Hz, 1H), 8.73(d, J=2 Hz, 1H), 8.77 (s, 1H), 8.81 (s, 1H), 9.01 (s, 1H), 10.28 (s,1H), 13.77 (brs, 1H), 14.04 (s, 1H); ESIMS found C₂₇H₂₃N₇OS m/z 494.1(M+H).

Example 2

The above synthesized compounds were screened using the assay procedurefor Wnt activity described below.

Reporter cell lines can be generated by stably transducing cells ofcancer cell lines (e.g., colon cancer) with a lentiviral construct thatinclude a wnt-responsive promoter driving expression of the fireflyluciferase gene.

Lentiviral constructs can be made in which the SP5 promoter, a promoterhaving eight TCF/LEF binding sites derived from the SP5 promoter, islinked upstream of the firefly luciferase gene. The lentiviralconstructs can also include a hygromycin resistance gene as a selectablemarker. The SP5 promoter construct can be used to transduce SW480 cells,a colon cancer cell line having a mutated APC gene that generates atruncated APC protein, leading to de-regulated accumulation ofβ-catenin. A control cell line can be generated using another lentiviralconstruct containing the luciferase gene under the control of the SV40promoter which does not require β-catenin for activation.

Cultured SW480 cells bearing a reporter construct can be distributed atapproximately 10,000 cells per well into 384 well multiwell plates.Compounds from a small molecule compound library can then be added tothe wells in half-log dilutions using a three micromolar topconcentration. A series of control wells for each cell type receive onlybuffer and compound solvent. Twenty-four hours after the addition ofcompound, reporter activity for luciferases can be assayed, for example,by addition of the BrightGlo luminescence reagent (Promega) and theVictor3 plate reader (Perkin Elmer). Readings can be normalized to DMSOonly treated cells, and normalized activities can then be used in theIC₅₀ calculations. Table 2 shows the activity of selected indazoleanalogs.

TABLE 2 Wnt inhibition Compound (μM) 1 0.14-0.15 2 0.125-0.146 30.083-0.179 4 0.013-0.040 5 0.067-0.098 6 0.010-0.013 7 0.214-0.463 9 0.4-0.63 10 0.0034-0.009  11 0.0035-0.065  12 0.006-0.008 150.010-0.025 16 0.164-0.200 20 0.0014-0.0018 24 0.066 31 0.005 86 0.02389 >10 90 0.012 91 0.002 94 0.011 97 0.001 99 >5 102 .004 104 0.007 1070.052 111 0.006 124 0.001 127 0.014 136 0.035 154 0.373 163 0.296 164 >6170 7 173 0.845 174 0.003 177 0.002 186 0.038 199 0.311 202 0.535 2050.041 211 0.42 214 0.042 217 0.039 247 0.002 252 0.650 257 0.095 2600.315 263 0.086 268 >10 274 >10 275 0.141 280 0.021 283 0.008 286 0.569289 0.002 291 0.002 293 0.191 295 0.003 301 0.069 303 1 304 0.003 3110.058 315 0.022 319 0.005 321 0.033 329 0.004 330 0.739 333 0.026 3360.055 339 0.039 342 0.020 346 0.002 349 0.022 373 0.005 397 0.0001

Example 3 Preparation of a Parenteral Suspension with a Compound ofFormula I for the Treatment of Bone/Cartilage Diseases

TABLE 3 Approximate solubility of a compound of Formula I MediaSolubility (μg/mL) 0.01N HCl 5 0.1N HCl 150 10 mM PBS pH 7.4 <0.05PBS/0.5% CMC/0.05% Tween80 0.3 PEG 400 8500 Propylene glycol 3700 EtOH4500 Ethyl acetate 80 DCM 35 Captex 300 C8/C10 Triglyceride 50

Dynamic vapor sorption shows up to 17.2% water is absorbed, showing thehygroscopicity of a compound of Formula I.

TABLE 4 Differential scanning calorimetry results for a compound ofFormula I Sample Dehydration Polymorphic change Melting Anhydrous N/A282.7° C. & 17.4 J/g 361° C. & 128.3 J/g API Hydrated 101° C. & 283.7°C. & 13.6 J/g 363° C. & 117.9 J/g API 309 J/g

Preparation of a 220 μg/mL suspension in 0.5% CMC/0.05% tween 80 beginsby dispensing 597 g±1 g of Gibco 1×PBS into the 1 L glass bottle. Usinga 1 mL sterile syringe, measure 0.3 mL of Tween 80. In a weigh boat,weigh out 3 g±0.1 g of Carboxymethyl Cellulose 7LXF PH (CMC). Startmixing the Tween80/PBS solution and slowly sprinkle the CMC into the 1 Lbottle containing the PBS/Tween mixture (increase mixing speed asnecessary). Once visually dispersed and the polymer is hydrated, startheating the container on a heating plate to promote phase inversion(turbidity). Once the solution is cool to the touch, filter NLT 120 mLinto the 250 mL glass bottle. Weigh 27 mg of a compound of Formula I andsuspend by mixing with the aid of 120 g of the sterile filteredCMC/tween solution. Fill 2 mL schott glass vials and 13 mm Fluroteccoated stoppers (West Pharma) and autoclave the vials at 260° F. for NLT25 minutes. Particle size measurement (Table 4) was performed afterautoclaving using a Horiba L-950.

TABLE 5 D(v, 0.1) D(v, 0.5) D(v, 0.9) 220 μg/mL suspension (autoclaved)1.5 μm 2.8 μm 4.9 μm

TABLE 6 % purity Concentration Osmolality pH Viscosity (HPLC) (HPLC) 220μg/mL 308 mOsm/kg 7.3 2.3 cP 99.0 226 μg/mL suspension (autoclaved)

Example 4 Preparation of a Parenteral Preparation with a Compound ofFormula I

Weigh 10 mg of a compound of Formula I (or its salt) and dissolve withthe aid of 10 mL of propylene glycol (USP grade), using aseptictechniques, sterile filter the solution using a millex GP syringe filterinto a sterile glass (type II) container. Before parenteraladministration, add 10 mL of the above solution in propylene glycol to avial containing 90 mL of sterile water, mix well.

Example 5 Preparation of a Suspension for Intravitreal Injection with aCompound of Formula I

Weigh 10 mg of micronized compound of Formula I (median particle size of5 μm) an added slowly while mixing to 100 mL of solution of 0.5%carboxymethyl cellulose (Aqualon 7LXF) and 0.05% tween 80 HP-LQ-MH(Croda) dissolved in PBS (Gibco, pH 7.4). The final suspension is loadedinto 2 mL glass vials and terminally sterilized by autoclaving.

It is also contemplated to heat sterilize the micronized compound ofFormula I and aseptic mixing with the sterile filtered solution of 0.5%carboxymethyl cellulose (Aqualon 7LXF) and 0.05% tween 80 HP-LQ-MH(Croda) dissolved in PBS (Gibco, pH 7.4).

Administration was performed using a 30 G needle and a volume ofapproximately 50 μL for intravitreal injection in rabbits, the presenceof the drug in the back of the eye (choroid/retina) was confirmed byLC/MS analysis after extraction using acetonitrile/formic acid solution.

Example 6

Composition for intratympanic injection with a compound of Formula I.

Weigh 10 mg of a compound of Formula I and dissolve with the aid of 100mL of propylene glycol (USP grade), using aseptic techniques, sterilefilter the solution using a millex GP syringe filter into a sterileglass (type II) container. Before parenteral administration, add 10 mLof the above solution in propylene glycol to a vial containing 90 mL ofsterile water, mix well.

Administration is performed using a 25 G needle and a volume ofapproximately 200 μL for intratympanic injection targeting the roundwindow membrane.

Example 7 Preparation of a Composition for Pulmonary Delivery with aCompound of Formula I for the Treatment of Pulmonary Fibrosis

Weigh 100 mg of a compound of Formula I (or its salt) an added slowlywhile mixing to 100 mL of solution of 1.5% dextrose (or lactose)+0.05%tyloxapol. The final solution is sterile filter the solution using amillex GP syringe filter.

Administration is performed using a jet nebulizer (Pari LC plus) or anaerodose nebulizer.

C57/Bl6 mice were dosed for 30 minutes via a nose only chamber (CHtechnology) at a flow rate of 15 LPM, particle size distribution anddose was measured by a 7 stage impactor (1 LPM) placed in one of theports. A median aerosol particle size of 1.2 μm with a GSD of 1.8 μm wasobtained and a dosing rate of 1.8 μM/min/mouse.

TABLE 7 Concentrations of a compound of Formula I in Mice (C57/Bl6)Inhalation Conc. (ng/mL) Time Point (h) Plasma Lung Ratio 0.25 188 1260067 2 132 7510 57 6 29.9 5225 175 23 453 2945 7

A diluted formulation of 0.5 mg/mL of compound of Formula I wasnebulized for 10 and 30 minutes to C57/bl6 mice (animals with bleomycininduced pulmonary fibrosis via the administration of bleomycin viaintratracheal administration), the compound of Formula I was deliveredvia a nose only chamber (CH technology) at a flow rate of 20 LPM dailyfor 14 days. At the end of the 14 days, the animals were tested forMMP-7 levels and the lungs were scored using the Ashcroft scoring systemto evaluate pulmonary fibrosis.

TABLE 8 Treatment Ashcroft Scoring MMP-7 levels (ng/mL) PBS/no dose 0.2510 Bleomycin/vehicle 3.04 13.6 Bleomycin/10 min aerosol 3.52 10.7 of acompound Formula I Bleomycin/30 min aerosol 2.08 9.4 of a compoundFormula I

Example 8 Preparation of a Suspension of Drug-Eluting Material with aCompound of Formula I

Solution 1 (PLGA containing active): Weigh 425 mg of PLGA 50:50 (PLGA0.55-0.75, Lactel B6010-2P)+4.5 mg of a compound of Formula I+4 mL ofdichloromethane, mix well to dissolve.

Solution 2 (1% PVA solution): Add 40 mL of DI water, then add 413 mg ofpolyvinyl alcohol (Sigma 87-89% hydrolyzed, PN 363170-25), mix todissolve then sterile filter through a 0.22μ, PES syringe filter(Millipore Millex GP).

PLGA microparticle formation: Add 20 mL of solution 2 into a cleansterile container, while mixing (high speed mixing) slowly add theentire 4 mL of solution 1 to solution 2.

The term “comprising” as used herein is synonymous with “including,”“containing,” or “characterized by,” and is inclusive or open-ended anddoes not exclude additional, unrecited elements or method steps.

What is claimed is:
 1. A polymorph of compound:

wherein the polymorph is a hydrate; and wherein the polymorph exhibitsan endotherm at about 283.7° C. as measured by differential scanningcalorimetry.
 2. The polymorph of a compound of claim 1, wherein thehydrate comprises up to about 17.2% water by weight.
 3. The polymorph ofa compound of claim 1, wherein the polymorph has a melting point ofabout 363° C.
 4. A polymorph of compound:

wherein the polymorph is anhydrous; and wherein the polymorph exhibitsan endotherm at about 282.7° C. as measured by differential scanningcalorimetry.
 5. The polymorph of a compound of claim 4, wherein thepolymorph has a melting point of about 361° C.